Biochemistry, Genetics and Molecular Biology › Molecular Biology

Cell death mechanisms and regulation

Works Count: 44409

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Description

This cluster of papers explores the molecular mechanisms, regulation, and implications of apoptosis and other forms of cell death, with a focus on the roles of Bcl-2 family proteins, mitochondria, TNF signaling, caspases, and reactive oxygen species. It also delves into the application of these insights in cancer therapy.

Keywords

Apoptosis; Cell Death; Bcl-2 Family; Mitochondria; TNF Signaling; Caspases; Reactive Oxygen Species; Necroptosis; Programmed Cell Death; Cancer Therapy

Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.

1992-11-01

Yasumasa Ishida , Yasutoshi Agata , Kei‐ichi Shibahara +1 more

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Cell Death: The Significance of Apoptosis

1980-01-01

A H Wyllie , J. F. R. Kerr , A Currie

Regulation of cell death: the calcium–apoptosis link

2003-07-01

Sten Orrenius , Boris Zhivotovsky , Pierluigi Nicotera

Cell Death

2004-01-01

Nika N. Danial , Stanley J. Korsmeyer

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The biochemistry of apoptosis

2000-10-01

Michael O. Hengartner

A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD

1998-01-01

Masato Enari , Hideki Sakahira , Hideki Yokoyama +3 more

Caspases: the executioners of apoptosis

1997-08-15

Gerald M. Cohen

Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for … Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1 beta-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Capases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.

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The Bcl-2 Protein Family: Arbiters of Cell Survival

1998-08-28

Jerry M. Adams , Suzanne Cory

REVIEW Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote … REVIEW Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.

Mammalian Caspases: Structure, Activation, Substrates, and Functions During Apoptosis

1999-06-01

William C. Earnshaw , L. Miguel Martins , Scott H. Kaufmann

▪ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past … ▪ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: (a) Zymogen gene transcription is regulated; (b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and (c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Two CD95 (APO-1/Fas) signaling pathways

1998-03-16

Carsten Scaffidi

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Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

1995-11-24

Zhengui Xia , Martin Dickens , Joël Raingeaud +2 more

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death … Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH 2 -terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.

Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009

2008-10-10

Guido Kroemer , Lorenzo Galluzzi , Peter Vandenabeele +7 more

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The BCL-2 protein family: opposing activities that mediate cell death

2007-12-21

Richard J. Youle , Andreas Strasser

Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death

2001-04-27

Michael C. Wei , Wei‐Xing Zong , Emily H. Cheng +7 more

Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a “BH3-domain–only” BCL-2 family member, … Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a “BH3-domain–only” BCL-2 family member, triggers the homooligomerization of “multidomain” conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak , but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a “multidomain” proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.

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Apoptosis in the Pathogenesis and Treatment of Disease

1995-03-10

Craig B. Thompson

In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the … In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.

Bcl-2 functions in an antioxidant pathway to prevent apoptosis

1993-10-01

David M. Hockenbery , Zoltán N. Oltvai , Xiao-Ming Yin +2 more

Apoptosis by Death Factor

1997-02-01

Shigekazu Nagata

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Apoptosis: A Review of Programmed Cell Death

2007-06-01

Susan A. Elmore

The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal … The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

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Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors

1998-08-01

Xu Luo , I. Imawati Budihardjo , Hua Zou +2 more

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Regulation of Cell Death Protease Caspase-9 by Phosphorylation

1998-11-13

Michael H. Cardone , Natalie Roy , Henning R. Stennicke +5 more

Caspases are intracellular proteases that function as initiators and effectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro–caspase-9 (pro-Casp9) in cells. Cytochrome c–induced proteolytic … Caspases are intracellular proteases that function as initiators and effectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro–caspase-9 (pro-Casp9) in cells. Cytochrome c–induced proteolytic processing of pro-Casp9 was defective in cytosolic extracts from cells expressing either active Ras or Akt. Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. Mutant pro-Casp9(Ser196Ala) was resistant to Akt-mediated phosphorylation and inhibition in vitro and in cells, resulting in Akt-resistant induction of apoptosis. Thus, caspases can be directly regulated by protein phosphorylation.

Death Receptors: Signaling and Modulation

1998-08-28

Avi Ashkenazi , Vishva M. Dixit

Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, … Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.

A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma

1997-08-01

Grazia Ambrosini , Colette Adida , Dario C. Altieri

The Fas Death Factor

1995-03-10

Shigekazu Nagata , Pierre Golstein

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas … Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition

2000-07-01

Chunying Du , Min Fang , Yucheng Li +2 more

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Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics

1972-08-01

J. F. R. Kerr , A H Wyllie , A Currie

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Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death

1990-11-01

David M. Hockenbery , Gabriel Núñez , Curt Milliman +2 more

Caspases: Enemies Within

1998-08-28

Nancy A. Thornberry , Yuri Lazebnik

REVIEW Apoptosis, an evolutionarily conserved form of cell suicide, requires specialized machinery. The central component of this machinery is a proteolytic system involving a family of proteases called caspases. These … REVIEW Apoptosis, an evolutionarily conserved form of cell suicide, requires specialized machinery. The central component of this machinery is a proteolytic system involving a family of proteases called caspases. These enzymes participate in a cascade that is triggered in response to proapoptotic signals and culminates in cleavage of a set of proteins, resulting in disassembly of the cell. Understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic gain.

Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis

1998-08-01

Honglin Li , Hong Zhu , Chi-jie Xu +1 more

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bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death

1993-08-01

Lawrence Boise , Maribel González‐García , C E Postema +6 more

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Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis

1995-07-01

Donald W. Nicholson , Ambereen Ali , Nancy A. Thornberry +7 more

Induction of apoptosis in fibroblasts by c-myc protein

1992-04-01

Gérard I. Evan , Andrew H. Wyllie , Christopher S. Gilbert +6 more

Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

1980-04-01

A H Wyllie

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

2005-05-15

Tilman Oltersdorf , Steven W. Elmore , Alexander R. Shoemaker +7 more

The Bcl2 family: regulators of the cellular life-or-death switch

2002-09-01

Suzanne Cory , Jerry M. Adams

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

2013-12-20

Peter E. Czabotar , Guillaume Lessène , Andreas Strasser +1 more

FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex

1996-06-01

Marta Muzio , Arul M. Chinnaiyan , Frank Kischkel +7 more

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Apoptosis, oncosis, and necrosis. An overview of cell death.

1995-01-01

Guido Majno , I Joris

Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

2005-05-29

Alexei Degterev , Zhihong Huang , Michael Boyce +7 more

Mitochondria and Apoptosis

1998-08-28

Douglas R. Green , John C. Reed

A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered … A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.

Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade

1997-11-01

Peng Li , Deepak Nijhawan , I. Imawati Budihardjo +4 more

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The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis

1997-02-21

Ruth M. Kluck , Ella Bossy‐Wetzel , Douglas R. Green +1 more

In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent … In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a caspase inhibitor, zVAD-fmk. In vitro, exogenous cytochrome c bypassed the inhibitory effect of Bcl-2. Cytochrome c release was unaccompanied by changes in mitochondrial membrane potential. Thus, Bcl-2 acts to inhibit cytochrome c translocation, thereby blocking caspase activation and the apoptotic process.

Identification and characterization of a new member of the TNF family that induces apoptosis

1995-12-01

Steven R. Wiley , Ken Schooley , Pamela J. Smolak +7 more

BCL-2 family members and the mitochondria in apoptosis

1999-08-01

Atan Gross , James M. McDonnell , S J Korsmeyer

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Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death

1993-08-01

Zoltán N. Oltval , Curt Milliman , Stanley J. Korsmeyer

Disruption of epithelial cell-matrix interactions induces apoptosis

1994-02-15

SM Frisch , H. Francis

Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate … Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell-matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis." Overexpression of bcl-2 protected cells against anoikis. Cellular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HT1080 cells or v-Ha-ras-transformed MDCK cells by reverse-transformation with adenovirus E1a; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.

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Ischemic Cell Death in Brain Neurons

1999-01-10

Peter Lipton

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell … This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell death occurs by a necrotic pathway characterized by either ischemic/homogenizing cell change or edematous cell change. Death also occurs via an apoptotic-like pathway that is characterized, minimally, by DNA laddering and a dependence on caspase activity and, optimally, by those properties, additional characteristic protein and phospholipid changes, and morphological attributes of apoptosis. Death may also occur by autophagocytosis. The cell death process has four major stages. The first, the induction stage, includes several changes initiated by ischemia and reperfusion that are very likely to play major roles in cell death. These include inhibition (and subsequent reactivation) of electron transport, decreased ATP, decreased pH, increased cell Ca(2+), release of glutamate, increased arachidonic acid, and also gene activation leading to cytokine synthesis, synthesis of enzymes involved in free radical production, and accumulation of leukocytes. These changes lead to the activation of five damaging events, termed perpetrators. These are the damaging actions of free radicals and their product peroxynitrite, the actions of the Ca(2+)-dependent protease calpain, the activity of phospholipases, the activity of poly-ADPribose polymerase (PARP), and the activation of the apoptotic pathway. The second stage of cell death involves the long-term changes in macromolecules or key metabolites that are caused by the perpetrators. The third stage of cell death involves long-term damaging effects of these macromolecular and metabolite changes, and of some of the induction processes, on critical cell functions and structures that lead to the defined end stages of cell damage. These targeted functions and structures include the plasmalemma, the mitochondria, the cytoskeleton, protein synthesis, and kinase activities. The fourth stage is the progression to the morphological and biochemical end stages of cell death. Of these four stages, the last two are the least well understood. Quite little is known of how the perpetrators affect the structures and functions and whether and how each of these changes contribute to cell death. According to this description, the key step in ischemic cell death is adequate activation of the perpetrators, and thus a major unifying thread of the review is a consideration of how the changes occurring during and after ischemia, including gene activation and synthesis of new proteins, conspire to produce damaging levels of free radicals and peroxynitrite, to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process. Although it is not fully established for all cases, the major driving force for the necrotic cell death process, and very possibly the other processes, appears to be the generation of free radicals and peroxynitrite. Effects of a large number of damaging changes can be explained on the basis of their ability to generate free radicals in early or late stages of damage. Several important issues are defined for future study. These include determining the triggers for apoptosis and autophagocytosis and establishing greater confidence in most of the cellular changes that are hypothesized to be involved in cell death. A very important outstanding issue is identifying the critical functional and structural changes caused by the perpetrators of cell death. These changes are responsible for cell death, and their identity and mechanisms of action are almost completely unknown.

Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c

1996-07-01

Xuesong Liu , Caryn Naekyung Kim , Jie Yang +2 more

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Molecular characterization of mitochondrial apoptosis-inducing factor

1999-02-01

Santos A. Susín , Hans K. Lorenzo , Naoufal Zamzami +7 more

Emerging roles of caspase-3 in apoptosis

1999-01-28

Alan G. Porter , Reiner U. Jänicke

Activation of apoptosis signalling pathways by reactive oxygen species

2016-09-17

Maureen Redza-Dutordoir , Diana A. Averill‐Bates

Caspase-14-like Proteases: An Epidermal Caspase and Its Evolutionarily Ancient Relatives

2025-06-22

Leopold Eckhart , Attila Placido Sachslehner , Julia Steinbinder +1 more | Biomolecules

Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively … Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively in epithelial cells and constitutively resides in its active form in the cornified layer of the human epidermis. Molecular phylogenetics has revealed that caspase-14 belongs to a subfamily of caspases, which also includes caspase-15 and -16. The latter are evolutionarily more ancient than caspase-14 and have been lost in the phylogenetic lineage leading to humans. Here, we review the molecular properties, the species distributions, and the biological roles of caspase-14-like proteases in amniotes. In contrast to the prodomain-less caspase-14, caspase-15 contains a prodomain that is predicted to assume a pyrin fold, and caspase-16 features a prodomain with unique sequence similarity to the catalytic domain. Gene knockout in mice, evolutionary gene loss in aquatic mammals and the association of human CASP14 mutations with ichthyosis indicate that caspase-14 is associated with the barrier function of mammalian skin. Caspase-15 is able to induce apoptosis in cell culture, but its role in vivo and the role of caspase-16 are currently unknown. We propose directions for research to further characterize caspase-14-like proteases.

Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac

2025-06-21

Yutaro Yamada , Mei Tsuchida , Takuya Noguchi +7 more | Cell Death Discovery

Abstract Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 … Abstract Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 in cell death induced by Fas/CD95. In BID knockout HeLa cells, inactivation of mitochondrial outer membrane permeabilization (MOMP) prevents Smac-induced inhibition of X-linked inhibitor of apoptosis (XIAP), causing resistance to Fas-induced apoptosis. However, reexpression of LKB1 in those cells naturally deficient for endogenous LKB1 restored apoptosis. Mechanistically, caspase-8 activated by Fas processed LKB1 to a truncated form, tLKB1. Both WT and kinase-inactive LKB1 antagonized XIAP to restore apoptosis, but somatic mutants of LKB1 found in Peutz-Jeghers syndrome (PJS) failed to do so. Thus, in addition to the known caspase-8 / tBid / Smac / XIAP pro-apoptotic axis, our results unveil a novel one, caspase-8 / tLKB1 / XIAP that potentially contributes to the antitumor functions of LKB1.

Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1

2025-06-20

Lior Soday , Chotima Seripracharat , Janine L. Gray +7 more | ACS Chemical Biology

Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen … Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated in vitro synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models in vivo. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells.

Dose-dependent apoptotic effect of Woodfordia fruticosa on hepatocellular carcinoma (HepG2) cells by upregulating bax and caspase-9

2025-06-20

Bing Kang , Kyubae Lee , Hyeon-Ju Lee +4 more | 3 Biotech

Radiobiological mechanisms of radium-223 dichloride: a nonclinical study

2025-06-20

Jin Young Baik , Yiseul Choi , E Lee +1 more | International Journal of Radiation Biology

This study aimed to elucidate the radiobiological mechanisms of radium-223 dichloride ([223Ra]RaCl2)-an FDA-approved agent for metastatic castration-resistant prostate cancer-by investigating its in vitro and in vivo toxic effects. Using both … This study aimed to elucidate the radiobiological mechanisms of radium-223 dichloride ([223Ra]RaCl2)-an FDA-approved agent for metastatic castration-resistant prostate cancer-by investigating its in vitro and in vivo toxic effects. Using both the CCK8 and clonogenic assays, our in vitro experiments evaluated the inhibition of cell proliferation in response to variations in applied activity and exposure duration in human cancer cell lines (MDA-MB-231, BxPC3, A549, and PC3) as well as in rat pancreatic cancer cells (AR42J). Molecular analyses utilizing SDS-PAGE characterized the activation of specific cell death pathways. Additionally, an in vivo investigation employing intravenous administration further examined the systemic toxicity of [223Ra]RaCl2 by monitoring animal mortality, body weight, and hematological parameters following treatment with varying activity levels (74, 148, and 222 kBq/head). [223Ra]RaCl2 significantly inhibited cell proliferation in an applied activity- and time-dependent manner in human cancer cell lines, whereas AR42J cells showed relative resistance. Molecular findings revealed that BxPC3 cells underwent apoptosis via caspase-3 cleavage; PC3 cells experienced pyroptosis marked by gasdermin E (GSDME) activation and caspase-7 cleavage; and MDA-MB-231 cells exhibited enhanced PARP-1 activation indicative of DNA double-strand breaks. In vivo, treated animals demonstrated significant differences in mortality, body weight, and hematological parameters compared to controls, mirroring myelosuppressive effects typical of radiotherapy. The findings provide critical insights into the differential cytotoxic mechanisms of [223Ra]RaCl2 across various cancer cell types and highlight its systemic toxicity in vivo. This improved understanding may facilitate the development of safer and more effective therapeutic radiopharmaceuticals based on [223Ra]RaCl2.

Yttrium oxide nanoparticles induce selective cytotoxicity, genomic instability and ROS mitochondrial P53 mediated apoptosis in human pancreatic cancer cells

2025-06-20

Hanan R. H. Mohamed , George M Hakeem , Yasmin Abdel Latif +5 more | Scientific Reports

Abstract Pancreatic cancer is a hard-to-treat tumor with a poor prognosis. While traditional pancreatic cancer therapies can be effective, issues like cytotoxicity, low selectivity, and drug resistance still pose major … Abstract Pancreatic cancer is a hard-to-treat tumor with a poor prognosis. While traditional pancreatic cancer therapies can be effective, issues like cytotoxicity, low selectivity, and drug resistance still pose major challenges. Nanotechnology has shown promise in improving cancer diagnosis and treatment. Yttrium oxide nanoparticles (Y 2 O 3 -NPs), for example, have demonstrated potent selective cytotoxicity against triple negative breast cancer cells; but their effects on pancreatic cancer cells have not been explored. This study aimed to explore the impact of Y 2 O 3 -NPs on cell proliferation, DNA integrity, and oxidative stress in pancreatic cancer (PANC-1) and human skin fibroblast (HSF) cells. The cytotoxicity of Y 2 O 3 -NPs after 72 h were estimated using Sulforhodamine (SRB) cytotoxicity assay, while alkaline Comet assay was done to study genomic DNA integrity. Generation level of reactive oxygen species (ROS) and integrity of mitochondrial membrane potential were also analyzed. Apoptosis induction was investigated using Flow Cytometry and expression level of apoptotic (p53), anti-apoptotic (Bcl2) and mitochondrial (ND3) genes was measured using quantitative RTPCR. Our findings exhibited that Y 2 O 3 -NPs had strong selective cytotoxicity against PANC-1 cells with an IC50 value of 31.06 µg/ml, while having minimal effect on normal HSF cells (IC50 = 319.21 µg/ml). Treatment of PANC-1 cells with Y 2 O 3 -NPs at the IC50 concentration for 72 h significantly increased intracellular ROS levels and DNA damage, along with a notable reduction in mitochondrial membrane potential. Additionally, a significant rise in necrotic, early, and late apoptotic cells was observed, accompanied by downregulation of the anti-apoptotic Bcl2 gene and upregulation of the apoptotic p53 and mitochondrial ND3 genes. These findings highlight the selective toxicity of Y 2 O 3 -NPs towards cancerous PANC-1 cells, with minimal impact on normal cells. Y 2 O 3 -NPs appear to induce apoptosis in cancer cells by increasing ROS generation, damaging DNA, disrupting mitochondrial function, and triggering cell death. This study suggests that Y 2 O 3 -NPs may be a promising candidate for pancreatic cancer treatment. Further research is needed to fully explore their therapeutic potential.

Analyzing the Structure-Activity Relationship of Necrostain-1 and Its Analogues as RIPK1 Inhibitors on Necroptosis

2025-06-20

Huilin Liu , Heng Wang , Huaixin Zheng +1 more | International Journal of Drug Discovery and Pharmacology

Necroptosis is a type of programmed cell death mediated by the RIPK1-RIPK3-MLKL axis. Receptor-interacting serine/threonine-protein kinase 1(RIPK1), the key upstream regulator of necroptosis, has been implicated in the pathogenesis of … Necroptosis is a type of programmed cell death mediated by the RIPK1-RIPK3-MLKL axis. Receptor-interacting serine/threonine-protein kinase 1(RIPK1), the key upstream regulator of necroptosis, has been implicated in the pathogenesis of various diseases, and its inhibitors are being tested in clinical trials. Necrostatin-1 (Nec-1), the firstly identified RIPK1 inhibitor, effectively prevents necroptosis by specifically inhibiting the kinase activity of RIPK1. In our study, we compared the inhibitory efficiency of Nec-1 and its analogues on RIPK1 by using the TBZ-induced necroptosis model in HT29 cells and analyzing their structure-activity relationship (SAR). The results showed that Nec-1, Nec-1s, Nec-a1, Nec-a2, Nec-a3, Nec-a4, and Nec-a5 exhibited potent inhibition of TBZ-induced necroptosis and phosphorylation of RIPK1, RIPK3, MLKL. Molecular docking showed that there were two potential binding pockets between Nec-1 and its analogues with RIPK1. SAR analysis showed that the type and size of a substituent at the nitrogen atom in the 3-position of the imidazolidine ring markedly influenced the activity, indicating that a substituent at this position is essential for maintaining the biological function. This study helps to further elucidate how Nec-1 works and could lead to the development of more effective analogues.

A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants

2025-06-19

Christine Farenc , P Clot , Salvatore Badalamenti +5 more | Advances in Therapy

Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study … Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1. This 2-part Phase I trial enrolled healthy participants aged 18-55 years. Part 1 consisted of 2 sub-parts. Part 1a was a double-blind, randomized, single ascending dose (SAD) study with 6 cohorts of 8 participants each randomized 3:1 to single oral dose of eclitasertib (10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or placebo. Part 1b was an open-label, randomized, three-sequence, cross-over design study to evaluate the relative bioavailability of the prototype formulation versus the drug substance and the effect of food in an independent cohort of 10 participants. Part 2 was a double-blind, randomized, multiple ascending dose study (MAD) with 4 cohorts of 10 participants each randomized 4:1 to receive eclitasertib (50 mg, 100 mg, 200 mg, or 600 mg once daily) or placebo orally for 14 days. Incidence of adverse events (AEs; primary outcome), PK (secondary outcome), and PD properties (exploratory outcome; assessed by reduction in levels of S166 phosphorylated RIPK1) were evaluated. Single and multiple oral doses of eclitasertib were well tolerated, with no study drug-related severe or serious AEs reported. Medical device-site reactions (includes AEs classified as device-site reaction, vessel puncture-site hematoma/pain, catheter-site pain/hematoma and catheter-site-related reactions) and headache were the most commonly reported AEs in both parts. Overall, the median Tmax ranged from 3 to 4 h. Cmax and AUC increased sub-dose proportionally. Administration of eclitasertib 100 mg following a high-fat meal did not significantly impact its bioavailability. At doses of 100 mg and above, > 90% inhibition of RIPK1 phosphorylation in human peripheral blood mononuclear cells was observed with eclitasertib at 12 h post-dose in both SAD and MAD studies. Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation. EudraCT 2019-001350-25.

Apoptosis Defects in Cancer and its Therapeutic Implications

2025-06-18

Jutishna Bora , Sayak Banerjee , Indrani Barman +3 more | BENTHAM SCIENCE PUBLISHERS eBooks

Apoptosis is the programmed cell death that regulates the cell survival or cell death balance in animals. Defects in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause … Apoptosis is the programmed cell death that regulates the cell survival or cell death balance in animals. Defects in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals mostly contribute to protecting the genomic integrity whereas defective apoptosis might lead to carcinogenesis. The signals of carcinogenesis alter the central points of the apoptotic pathways, which include the FLICE-inhibitory protein (c-FLIP) and the inhibitor of apoptosis (IAP) proteins. The tumor cells trigger the expression of antiapoptotic proteins such as Bcl-2 or downregulate the proapoptotic proteins like BAX. Most of these changes lead to intrinsic resistance to the most common anticancer therapy, chemotherapy. Apoptosis-resistant cells and transduction pathways that inhibit apoptosis can stimulate non-apoptotic mechanisms of cell death and senescence; this preserves the antitumor effect of several anticancer agents. The development of some promising cancer treatment strategies has been discussed below, which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for the induction of apoptosis.

Antineoplastic activity of a novel tri-specific single chain antibody targeting the hERG1/β1 integrin complex and TRAIL receptors

2025-06-18

Claudia Duranti , Jessica Iorio , Chiara Capitani +7 more | Molecular Cancer Therapeutics

Abstract Targeted therapies and immunotherapies have largely improved cancer treatment in the last years. One of the most promising approaches is the induction of tumor apoptosis by the Tumor Necrosis … Abstract Targeted therapies and immunotherapies have largely improved cancer treatment in the last years. One of the most promising approaches is the induction of tumor apoptosis by the Tumor Necrosis Factor (TNF) Related Apoptosis Inducing Ligand (TRAIL) through its binding to apoptosis-inducing receptors DR4 and DR5 on the plasma membrane of target cells. However, some constraints (e.g. the short in vivo half-life, the poor activity on DR5 receptors) hinder the use of naked, soluble forms of TRAIL. Previous studies have shown that fusing TRAIL sequences with antibody-based moieties may represent a novel and efficacious strategy to overcome such hindrances. On these bases, novel TRAIL-related anticancer therapeutic strategies are being developed. In the present paper we describe a novel antibody represented by a single chain diabody directed against a cancer-specific target, i.e. the hERG1/β1 integrin complex-scDb-hERG1-β1- fused with three TRAIL sequences. The scDb-hERG1-b1-TRAIL antibody combines the specific targeting and the down regulation of cancer-specific signaling pathways by the scDb-hERG1-b1 with the pro-apoptotic activity triggered by TRAIL. We provide substantial evidence of the efficacy of the scDb-hERG1-b1-TRAIL antibody to decrease tumor growth triggering apoptotic cell death in vitro in Breast Cancer (BCa) cells as well as in vivo in a mouse model of Triple Negative BCa (TNBCa). Being characterized by a favorable pharmacokinetic and toxicity profile, the scDb-hERG1-b1-TRAIL antibody can be proposed for the treatment of difficult to treat cancers, such as TNBCa, which express the hERG1/β1 complex and TRAIL receptors.

Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule

2025-06-18

S.-L. Chen , Szu-Ying Wu , Yun-Xun Chang +6 more | Cell Death and Disease

Phase Ib basket expansion trial and alternative-schedule dose-escalation study of ATR inhibitor elimusertib in advanced solid tumors with DNA damage response defects

2025-06-14

Timothy A. Yap , David S.P. Tan , Anastasios Stathis +7 more | Cancer Discovery

Abstract In this Phase Ib basket expansion trial and alternative-schedule dose-escalation study, we evaluated the ATR inhibitor elimusertib at 40 mg twice daily (3 days on/4 days off) in 143 … Abstract In this Phase Ib basket expansion trial and alternative-schedule dose-escalation study, we evaluated the ATR inhibitor elimusertib at 40 mg twice daily (3 days on/4 days off) in 143 patients with advanced cancer with tumor-associated DNA damage response defects, comprising gynecologic (n=45), prostate (n=19), colorectal (n=24), and breast (n=19) cancer, and ATM loss (n=36). An alternative schedule (3 days on/11 days off) was assessed in patients with ATM loss and/or ATM mutations (n=32). Elimusertib-related reversible hematologic toxicities were observed. Objective responses were modest (4.5%), but a disease control rate (DCR) of 49.3% indicated that subpopulations of patients, especially with gynecologic cancers (DCR 59.5%), derived meaningful durable benefit from elimusertib. There was no association between ATM protein loss or ATM alterations and progression-free survival or overall response. Further studies to define optimal predictive biomarkers for ATR inhibitors as monotherapy and in combination are ongoing.

Energizing leukaemia

2025-06-11

Anna Dart | Nature reviews. Cancer

Polymersomal vincristine-PLK1 inhibitor boosts immunogenic cell death and antitumor immunity

2025-06-10

Yan Zha , Li Cao , Songsong Zhao +5 more | Chemical Engineering Journal

Inhibition of virally induced TFEB proteasomal degradation as a host-centric therapeutic approach for coronaviral infection

2025-06-06

Travis Lear , Mads Larsen , Bo Lin +7 more | Science Advances

The endolysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a previously unidentified aspect … The endolysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a previously unidentified aspect of coronaviral infection, whereby the master transcriptional activator of lysosomal homeostasis-TFEB-is targeted for proteasomal-mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased small interfering RNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. We derive a series of novel small molecules that interfere with the DCAF7-TFEB interaction. These agents inhibit virus-induced TFEB degradation and demonstrate broad antiviral activities including attenuating severe acute respiratory syndrome coronavirus 2 infection in two animal models. Together, these results delineate a virally triggered pathway that impairs lysosomal homeostasis in the host. Small molecule E3 ubiquitin ligase DCAF7 inhibitors that restore lysosomal function represent a novel class of host-directed, antiviral therapies useful for current and potentially future coronaviral variants.

Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases

2025-06-04

Tom Nguyen , Hong-Toan Lai , Romain Fernandes +4 more | Cell Communication and Signaling

Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participates … Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participates in mitochondrial bioenergetics through interaction with its partner coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) and involvement in mitochondrial protein import. These dual roles place AIF between pro-survival and pro-death cell fate decisions. In this review, we first describe the structure and the dual functions of AIF, highlighting its structure-function relationships. We then report previously identified AIFM1 mutations and their clinical phenotypes. Finally, we discuss the relevance of AIF in cancer and the potential of targeting this protein for the treatment of cancer.

Designing an apoptosis reporter by mutagenesis-based insertion of caspase-3 cleavage motif into green fluorescence protein

2025-06-01

Dong Gil Lee , Hae-Jun Yang , Unbin Chae +7 more | Journal of Advanced Research

A Medicinal Chemistry Perspective on ATR: Current Status and Future Directions

2025-06-01

Kun Li , Xiangxi Sun , Shengyu Liu +3 more | European Journal of Medicinal Chemistry

Bisleuconothine A as a potential plasma alpha-2-macroglobulin ligand and apoptosis inducer in glioma: Structural and functional insights

2025-06-01

Xuechao Dong , Bo Liu , Xuan-Yu Tan +1 more | International Journal of Biological Macromolecules

ABS0223 PROFILING OF MT-3534, A HUMANIZED MONOCLONAL ANTIBODY TARGETING PAD4, AS A CANDIDATE DRUG FOR THE TREATMENT OF RA

2025-06-01

Hatsumi Niki , A. Nishizawa , Yasuo Ono +6 more | Annals of the Rheumatic Diseases

ATR-mediated phosphorylation of RIPK1 inhibits DNA damage-induced necroptosis

2025-06-01

Shen-Nan Shi , Qiuyang Xu , Xiaofei Jiao +7 more | Biochemical Pharmacology

Investigation of the Combined Effect of Protons and the Chemotherapy Drug Doxorubicin on the Expression of BIRC5 (Survivin) Genes and PMAIP1 (Noxa) in MCF-7 Cells

2025-06-01

A.A. Melnikova , А. А. Афонин , L.N. Komarova +1 more | Medical Radiology and radiation safety

Purpose: Analysis of PMAIP1 and BIRC5 gene expression in breast cancer cells after proton exposure, both as monotherapy and in combination with doxorubicin. Material and methods: The object of the … Purpose: Analysis of PMAIP1 and BIRC5 gene expression in breast cancer cells after proton exposure, both as monotherapy and in combination with doxorubicin. Material and methods: The object of the study was MCF-7 cells. Four study groups were formed: a group exposed to ionizing radiation; a group treated with doxorubicin; a group of combined exposure to ionizing radiation and doxorubicin; and an untreated control group. The cells were irradiated at the Prometheus proton radiation complex at the A.F. Tsyb MRSC, with a scanning proton beam at a dose of 4 Gy (proton energy of 100 MeV) in the center of the distributed Bragg peak. The cells were treated with the chemotherapy drug doxorubicin at a concentration of 0.004 mg/ml 24 hours before irradiation. Total RNA was isolated using an RNA Solo kit and quantified spectrophotometrically (NanoDrop ND-1000). Reverse transcription and amplification were performed simultaneously in real time using the OneTube RT-PCR kit with SYBR Green I as a fluorescent indicator. Results: The analysis showed that doxorubicin suppresses the expression of BIRC5 (up to 0.02), which is consistent with its known apoptogenic activity. However, the combined effect of doxorubicin and radiation leads to an increase in BIRC5 expression (up to 0.63) and a simultaneous decrease in PMAIP1 expression (up to 0.0003). This indicates the launch of complex compensatory cell survival mechanisms aimed at suppressing apoptosis and enhancing DNA repair under conditions of combined cytotoxic stress. A less pronounced decrease in BIRC5 expression during ionizing radiation monotherapy (up to 0.16) compared with doxorubicin (0.02) is probably due to differences in the nature and kinetics of DNA damage induced by these agents. The data obtained indicate the nonlinear nature of the cellular response to combined exposure and emphasize the difficulty of predicting the effectiveness of combined radiotherapy. Conclusion: The results demonstrate the antagonistic interaction of doxorubicin and ionizing radiation in the regulation of apoptosis in MCF-7 cells, emphasizing the need for further research to optimize combination cancer therapy.

Unravelling the pathological roles of anastasis in cancer recurrence

2025-06-01

Ho Man Tang , Ho Lam Tang | Open Biology

Can anastasis contribute to cancer recurrence? Anastasis is a cell recovery mechanism to spare dying cells after the initiation of the cell death process. Emerging studies interrogate anastasis as an … Can anastasis contribute to cancer recurrence? Anastasis is a cell recovery mechanism to spare dying cells after the initiation of the cell death process. Emerging studies interrogate anastasis as an unexpected escape tactic for cancer cells to evade cell death-inducing anti-cancer therapy, leading to recurrence. After anastasis, cancer cells display increased invasiveness and genomic instability, which could be associated with the common and fatal features of metastasis and drug resistance at the cancer recurrence. These studies open an encouraging new conceptual avenue for arresting cancer recurrence by targeting anastasis in cancer cells after conventional anti-cancer therapy. Here, we highlight recent findings towards unravelling pathological roles of anastasis in cancer recurrence, for the purpose of stimulating ideas and promoting the development of this new field of cancer research.

Necroptosis in Sepsis: Mechanisms and Therapeutic Potential

2025-06-01

Lu Wang , Yuan Cao , Yiqi Wu +7 more | Cytokine & Growth Factor Reviews

Steamed panax notoginseng mitigates CA-MRSA USA300-induced necroptosis in human neutrophils

2025-05-30

Lulu Zhang , Xiaoyu Feng , H. An +7 more | Frontiers in Pharmacology

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) disrupts innate immunity by inducing necroptosis in polymorphonuclear neutrophils (PMNs), a process linked to excessive inflammation and tissue damage. CA-MRSA releases virulence factors that enhance … Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) disrupts innate immunity by inducing necroptosis in polymorphonuclear neutrophils (PMNs), a process linked to excessive inflammation and tissue damage. CA-MRSA releases virulence factors that enhance its pathogenicity by disrupting the host's innate immune response, particularly impairing the phagocytic function of PMNs. Steamed Panax notoginseng (S-PN), a traditional Chinese medicine (TCM), has demonstrated immune-regulatory and anti-inflammatory properties, showing promising therapeutic effects in alleviating the severe inflammatory responses induced by pathogenic microbial infections. This study aims to investigate the pharmacological effects and mechanisms of S-PN alleviating CA-MRSA-induced PMN necroptosis by suppressing MRSA virulence factors and inhibiting the RIPK1/RIPK3/MLKL signaling pathway, thereby attenuating inflammatory damage. A co-culture model of MRSA USA300 strain and PMNs isolated from healthy human blood was established to observe the changes in necroptosis marker HMGB1, PMNs counts, ROS, chemokine MCP-1 and pro-inflammatory cytokines IL-1β, IL-8, TNF-α. RNA-seq was employed to analyze the effects of S-PN on the transcriptional expression of pathogenesis-related genes of MRSA. RT-PCR was utilized to validate the expression of S-PN on MRSA virulence factors and PMNs necroptosis related genes. S-PN significantly inhibited HMGB1, ROS, MCP-1, IL-1β and IL-8 in MRSA-PMN co-cultures, the PMN count in the S-PN group was higher than that in the model group. S-PN downregulated MRSA pathogenic-associated S. aureus infection and quorum sensing signaling pathways, and significantly reduced the virulence factors PSM and PVL. S-PN suppressed the expression of genes associated with necroptosis ripk1, ripk3, and mlkl in PMNs. S-PN alleviates CA-MRSA infection-induced immune damage through dual mechanisms: suppression of bacterial virulence factors (PSM and PVL) and inhibition of PMNs necroptosis. These findings underscore its potential as a complementary therapeutic strategy against CA-MRSA infections, providing a theoretical foundation for integrating TCM into adjuvant treatments for drug-resistant bacterial infections.

Cucurbitacin B induces oral squamous cell carcinomapyroptosis via GSDME and inhibits tumour growth

2025-05-27

Xin Chen , Mengyuan Yang , Heng Zhang +7 more

Tetrahedral framework nucleic acids loaded with chrysophanol for the treatment of chronic kidney disease

2025-05-27

Xiaoshuai Gao , Dexuan Xiao , Wei Wang +5 more

Withdrawal notice to “ATR-mediated phosphorylation of RIPK1 inhibits DNA damage-induced necroptosis” [Biochemical Pharmacology 237 (2025) 116949]

2025-05-26

Shen-Nan Shi , Qiuyang Xu , Xiaofei Jiao +7 more

Chemical profiling and anticancer activity of Alnus incana dichloromethane fraction on HeLa cells via cell cycle arrest and apoptosis

2025-05-26

Walaa Hesham , Emad M. Elzayat , Mohamed Hosney +1 more

Research progress of ATR small molecule inhibitors in cancer therapy

2025-05-24

Shujin Guo , Q. He , Yuping Liu +5 more

Potential reverse functions of GOLPH3 and GOLPH3L in pyroptotic cell death, with implications in resistance to radiotherapy and chemotherapy

2025-05-22

Çağlar Berkel

The nuclear phosphoinositide-p53 signalosome in the regulation of cell motility

2025-05-22

Xiaoting Hou , Yu Chen , Bo Zhou +7 more

Abstract Dysregulation of p53 and phosphoinositide (PIPn) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the … Abstract Dysregulation of p53 and phosphoinositide (PIPn) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the nucleus to form a PIPn-p53 signalosome that modulates nuclear AKT activation and downstream signaling, thereby influencing cancer cell survival and motility. This review examines recent insights into nuclear PIPn signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIPns interact with p53 to form signalosomes that affect cell motility. We emphasize the critical role of PIPns in stabilizing p53 and activating de novo nuclear AKT signaling, which subsequently modulates key motility-related pathways. Understanding the unique operation and function of the PIPn-p53 signalosome in nuclear phosphatidylinositol 3-kinase (PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.

Integration of past caspase activity biases cell elimination in vivo

2025-05-20

T. Cumming , Alexis Villars , Anđela Davidović +3 more

Abstract The fine tuning of apoptosis in epithelia is essential for regulating tissue size, shape, homeostasis and the maintenance of sealing properties. Regulation of cell death is mostly orchestrated by … Abstract The fine tuning of apoptosis in epithelia is essential for regulating tissue size, shape, homeostasis and the maintenance of sealing properties. Regulation of cell death is mostly orchestrated by the activation of Caspases, proteases which were long thought to trigger an irreversible engagement in cell death. However, recent data in vivo and in vitro outline numerous non-apoptotic functions of caspases as well as quite ubiquitous sublethal activation of effector caspases during development. Yet, it remains unclear in many instances what drives the bifurcation between cell death engagement and cell survival upon caspase activation. The existence of a caspase activity threshold was generally considered to underpin this binary decision, but this was never assessed quantitatively in vivo especially at the single cell level. Using quantitative live imaging combined with machine learning and optogenetics in the Drosophila pupal notum (a single layer epithelium), we reveal for the first time the existence of a large heterogeneity of caspase sensitivity between cells, as well as the existence of distinct spatial domains with low or high sensitivity to caspases. Using correlative and perturbative experiments, we outline the central role of past exposure to sublethal caspase activity which sensitises cells for apoptosis for several hours. Integrating information about past caspase activation is sufficient to explain most of the global pattern of caspase sensitivity and predict at the single cell level which cells will engage in apoptosis. Finally, we demonstrate that past sublethal caspase activation in a subset of cells is sufficient to bias cell elimination at the clonal and single cell level, thus revealing an alternative mechanism of physiological cell competition. Altogether, this work reveals for the first time the existence of a new layer of apoptosis regulation in vivo downstream of effector caspases which can be developmentally regulated and bias clonal selection and the spatial pattern of cell death.

Caspase Domain Duplication During the Evolution of Caspase-16

2025-05-20

Leopold Eckhart , Attila Placido Sachslehner , Julia Steinbinder +1 more

Abstract Caspases are cysteine-dependent aspartate-directed proteases which have critical functions in programmed cell death and inflammation. Their catalytic activity depends on a catalytic dyad of cysteine and histidine within a … Abstract Caspases are cysteine-dependent aspartate-directed proteases which have critical functions in programmed cell death and inflammation. Their catalytic activity depends on a catalytic dyad of cysteine and histidine within a characteristic protein fold, the so-called caspase domain. Here, we investigated the evolution of caspase-16 (CASP16), an enigmatic member of the caspase family, for which only a partial human gene had been reported previously. The presence of CASP16 orthologs in placental mammals, marsupials and monotremes suggests that caspase-16 originated prior to the divergence of the main phylogenetic clades of mammals. Caspase-16 proteins of various species contain a carboxy-terminal caspase domain and an amino-terminal prodomain predicted to fold into a caspase domain-like structure, which is a unique feature among caspases known so far. Comparative sequence analysis indicates that the prodomain of caspase-16 has evolved by the duplication of exons encoding the caspase domain, whereby the catalytic site was lost in the amino-terminal domain and conserved in the carboxy-terminal domain of caspase-16. The murine and human orthologs of CASP16 contain frameshift mutations and therefore represent pseudogenes ( CASP16P ). CASP16 of the chimpanzee displays more than 98% nucleotide sequence identity with the human CASP16P gene but, like CASP16 genes of other primates, has an intact protein coding sequence. We conclude that caspase-16 structurally differs from other mammalian caspases, and the pseudogenization of CASP16 distinguishes humans from their phylogenetically closest relatives.

Partial mitochondrial involvement in the antiproliferative and immunostimulatory effects of PT-112

2025-05-19

Ruth Soler-Agesta , Manuel Beltrán‐Visiedo , Ai Sato +7 more

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. … PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects.

Specific signaling pathways mediated programmed cell death in tumor microenvironment and target therapies

2025-05-16

Cheng‐Peng Sun , Jiawei Gui , Yilei Sheng +3 more

Increasing evidence has shown that programmed cell death (PCD) plays a crucial role in tumorigenesis and cancer progression. The components of PCD are complex and include various mechanisms such as … Increasing evidence has shown that programmed cell death (PCD) plays a crucial role in tumorigenesis and cancer progression. The components of PCD are complex and include various mechanisms such as apoptosis, necroptosis, alkaliptosis, oxeiptosis, and anoikis, all of which are interrelated in their functions and regulatory pathways. Given the significance of these processes, it is essential to conduct a comprehensive study on PCD to elucidate its multifaceted nature. Key signaling pathways, particularly the caspase signaling pathway, the RIPK1/RIPK3/MLKL pathway, and the mTOR signaling pathway, are pivotal in regulating PCD and influencing tumor progression. In this review, we briefly describe the generation mechanisms of different PCD components and focus on the regulatory mechanisms of these three major signaling pathways within the context of global PCD. Furthermore, we discuss various tumor therapeutic compounds that target different signaling axes of these pathways, which may provide novel strategies for effective tumor therapy and help improve patient outcomes in cancer treatment.