有丝分裂细胞死亡

细胞死亡有坏死、凋亡、裂亡、自体吞噬等多种方式。细胞裂亡指细胞经过一次有丝分裂后才开始死亡的现象。本文综述了对于细胞裂亡这种新型细胞死亡方式的初步认识。     

Cell death by necrosis: towards a molecular definition

Necrosis has been defined as a type of cell death that lacks the features of apoptosis and autophagy, and is usually considered to be uncontrolled. Recent research suggests, however, that its occurrence and course might be tightly regulated. After signaling- or damage-induced lesions, necrosis can include signs of controlled processes such as mitochondrial dysfunction, enhanced generation of reactive oxygen species, ATP depletion, proteolysis by calpains and cathepsins, and early plasma membrane rupture. In addition, the inhibition of specific proteins involved in regulating apoptosis or autophagy can change the type of cell death to necrosis. Because necrosis is prominent in ischemia, trauma and possibly some forms of neurodegeneration, further biochemical comprehension and molecular definition of this process could have important clinical implications.     

Programmed cell death pathways in cancer: a review of apoptosis,autophagy and programmed necrosis

Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro‐survival or pro‐death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti‐cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis‐related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment.     

Interconnections between apoptotic,autophagic and necrotic pathways: implications for cancer therapy development

The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer‐ and anti‐ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia‐induced damage. However, initial clinical studies on apoptosis‐modulating drugs led to unexpected results in different clinical conditions and this may have been due to co‐effects on non‐apoptotic interconnected cell death mechanisms and the ‘yin‐yang’ role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways (e.g. Bcl2‐family members and p53). We also briefly highlight stress‐induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation‐induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.     

Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus

Macroautophagy has been implicated as a mechanism of cell death. However, the relationship between this degradative pathway and cell death is unclear as macroautophagy has been shown recently to protect against apoptosis. To better define the interplay between these two critical cellular processes, we determined whether inhibition of macroautophagy could have both pro-apoptotic and anti-apoptotic effects in the same cell. Embryonic fibroblasts from mice with a knock-out of the essential macroautophagy gene atg5 were treated with activators of the extrinsic and intrinsic death pathways. Loss of macroautophagy sensitized these cells to caspase-dependent apoptosis from the death receptor ligands Fas and tumor necrosis factor-alpha (TNF-alpha). Atg5-/- mouse embryonic fibroblasts had increased activation of the mitochondrial death pathway in response to Fas/TNF-alpha in concert with decreased ATP levels. Fas/TNF-alpha treatment failed to up-regulate macroautophagy, and in fact, decreased activity at late time points. In contrast to their sensitization to Fas/TNF-alpha, Atg5-/- cells were resistant to death from menadione and UV light. In the absence of macroautophagy, an up-regulation of chaperone-mediated autophagy induced resistance to these stressors. These results demonstrate that inhibition of macroautophagy can promote or prevent apoptosis in the same cell and that the response is governed by the nature of the death stimulus and compensatory changes in other forms of autophagy. Experimental findings that an inhibition of macroautophagy blocks apoptosis do not prove that autophagy mediates cell death as this effect may result from the protective up-regulation of other autophagic pathways such as chaperone-mediated autophagy.     

Hid can induce, but is not required for autophagy in polyploid larval Drosophila tissues

The major cell death pathways are apoptosis and autophagy-type cell death in Drosophila. Overexpression of proapoptotic genes in developing imaginal tissues leads to the activation of caspases and apoptosis, but most of them show no effect on the polytenic cells of the fat body during the last larval stage. Surprisingly, overexpression of Hid induces caspase-independent autophagy in the fat body, as well as in most other larval tissues tested. Hid mutation results in inhibition of salivary gland cell death, but the disintegration of the larval midgut is not affected. Electron microscopy shows that autophagy is normally induced in fat body, midgut and salivary gland cells of homozygous mutant larvae, suggesting that Hid is not required for autophagy itself. Constitutive expression of the caspase inhibitor p35 produces identical phenotypes. Our results show that the large, post-mitotic larval cells do not react or activate autophagy in response to the same strong apoptotic stimuli that trigger apoptosis in small, mitotically active imaginal disc cells.     

Steroid-triggered death by autophagy

Programmed cell death is a critical part of normal development, removing obsolete tissues or cells and sculpting body parts to assume their appropriate form and function. Most programmed cell death occurs by apoptosis of individual cells or autophagy of groups of cells. Although these pathways have distinct morphological characteristics, they also have a number of features in common, suggesting some overlap in their regulation. A recent paper by Lee and Baehrecke provides further support for this proposal.(1) These authors present, for the first time, a genetic analysis of autophagy, using the steroid-triggered metamorphosis of Drosophila as a model system. They demonstrate a remarkable degree of overlap between the control of apoptosis and autophagy as well as a key role for the steroid-inducible gene E93 in directing the autophagic death response. This paper also shows that E93 can direct cell death independently from the known death-inducer genes, defining a novel death pathway in Drosophila.     

Targeting of cancer cell death mechanisms by resveratrol: a review

Cancer cell death is the utmost aim in cancer therapy. Anti-cancer agents can induce apoptosis, mitotic catastrophe, senescence, or autophagy through the production of free radicals and induction of DNA damage. However, cancer cells can acquire some new properties to adapt to anti-cancer agents. An increase in the incidence of apoptosis, mitotic catastrophe, senescence, and necrosis is in favor of overcoming tumor resistance to therapy. Although an increase in the autophagy process may help the survival of cancer cells, some studies indicated that stimulation of autophagy cell death may be useful for cancer therapy. Using some low toxic agents to amplify cancer cell death is interesting for the eradication of clonogenic cancer cells. Resveratrol (a polyphenol agent) may affect various signaling pathways related to cell death. It can induce death signals and also downregulate the expression of anti-apoptotic genes. Resveratrol has also been shown to modulate autophagy and induce mitotic catastrophe and senescence in some cancer cells. This review focuses on the important targets and mechanisms for the modulation of cancer cell death by resveratrol.

     

The role of cell signalling in the crosstalk between autophagy and apoptosis

Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be identified has taken centre stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Apoptosis has been extensively studied and its contribution to the pathogenesis of disease well documented. However, apoptosis does not function alone in determining the fate of a cell. More recently, autophagy, a process in which de novo formed membrane enclosed vesicles engulf and consume cellular components, has been shown to engage in complex interplay with apoptosis. As a result, cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II cell death is not completely clear and as we will discuss in this review and perhaps a discrete difference does not exist, due to intrinsic factors among different cell types and crosstalk among organelles within each cell type. Apoptosis may begin with autophagy and autophagy can often end with apoptosis, inhibition or a blockade of caspase activity may lead a cell to default into Type II cell death from Type I.     

Autophagic cell death unraveled: Pharmacological inhibition of apoptosis and autophagy enables necrosis

Apoptosis is a well-characterized pathway to cell death, yet how it is related to other forms of cell death such as necrosis, and possibly also autophagic cell death has not been entirely clear. Difficulties arise because necrotic cell death is poorly characterized at the molecular level, and also because autophagy is primarily a survival pathway that has been associated with cell death induction in some circumstances. A common theme appears to be now emerging where autophagy promotes survival of apoptosis-defective cells, and inhibition of the autophagy survival function in this setting represents a means to divert cells into a necrotic cell fate. In cells denied the ability to commit suicide by apoptosis, and that are also unable to access the autophagy survival mechanism to sustain homeostasis, necrosis is the default activity. This was most recently illustrated with the discovery that the caspase and apoptosis inhibitor, zVAD, also inhibits a lysosomal protease, and thereby autophagy, and it is this dual inhibition that is responsible for induction of necrotic cell death.(1) This radically alters the interpretation of earlier findings reporting induction of autophagic cell death by zVAD,(2) instead, suggests that autophagy functions to promote cell survival.     

Caspase-independent cell deaths

A very common and the best understood of the mechanisms of physiological cell death is apoptosis, resulting from the activation, through either of two primary pathways, of site-specific proteases called caspases. There are, however, many other routes to cell death, prominently including autophagy and proteasomal degradation of critical constituents of cells. These routes are frequently seen in experimental situations in which initiator or effector caspases are inhibited or blocked through genetic means, but they are also encountered during normal physiological and pathological processes. Most frequently, autophagic or proteasomal degradation is used to eliminate massive cytoplasm of very large cells, especially post-mitotic cells, and these pathways are prominent even though caspase genes, messages, and pro-enzymes are found in the cells. These forms of cell death are fully physiological and not simply a default pathway for a defective cell; and they are distinct from necrosis. We do not yet understand the extent to which the pathways are linked, what mechanisms trigger the caspase-independent deaths, and how the choices are made.     

Controlled Necrosis

Some necrosis mechanisms are considered. Although traditionally necrosis is considered as an uncontrolled and catastrophic cell death caused by intense damaging impacts, last data have shown that necrosis may occur in some physiological processes. Moreover, necrosis may be controlled by the intracellular signaling processes. For example, experiments with photodynamic treatment of neurons and surrounding glial cells have shown that increase in plasma membrane permeability leading to necrosis is controlled by neurotrophins, Ca²⁺-, cAMP-, and cGMP-dependent signaling pathways. An assortment of signaling proteins involved in these responses are different in neurons and glial cells. Thus, necrosis is uncontrolled under very strong impacts. However, necrotic processes induced by moderate impacts may be controlled by the cellular signaling system. Moreover, in some physiological situations necrosis may be performed according to the predetermined program.     

Shaping organisms with apoptosis

Programmed cell death is an important process during development that serves to remove superfluous cells and tissues, such as larval organs during metamorphosis, supernumerary cells during nervous system development, muscle patterning and cardiac morphogenesis. Different kinds of cell death have been observed and were originally classified based on distinct morphological features: (1) type I programmed cell death (PCD) or apoptosis is recognized by cell rounding, DNA fragmentation, externalization of phosphatidyl serine, caspase activation and the absence of inflammatory reaction, (2) type II PCD or autophagy is characterized by the presence of large vacuoles and the fact that cells can recover until very late in the process and (3) necrosis is associated with an uncontrolled release of the intracellular content after cell swelling and rupture of the membrane, which commonly induces an inflammatory response. In this review, we will focus exclusively on developmental cell death by apoptosis and its role in tissue remodeling.     

Features of autophagic cell death in Plasmodium liver-stage parasites

Analyzing molecular determinants of Plasmodium parasite cell death is a promising approach for exploring new avenues in the fight against malaria. Three major forms of cell death (apoptosis, necrosis and autophagic cell death) have been described in multicellular organisms but which cell death processes exist in protozoa is still a matter of debate. Here we suggest that all three types of cell death occur in Plasmodium liver-stage parasites. Whereas typical molecular markers for apoptosis and necrosis have not been found in the genome of Plasmodium parasites, we identified genes coding for putative autophagy-marker proteins and thus concentrated on autophagic cell death. We characterized the Plasmodium berghei homolog of the prominent autophagy marker protein Atg8/LC3 and found that it localized to the apicoplast. A relocalization of PbAtg8 to autophagosome-like vesicles or vacuoles that appear in dying parasites was not, however, observed. This strongly suggests that the function of this protein in liver-stage parasites is restricted to apicoplast biology.     

Time-Dependent Changes in Apoptosis Upon Autophagy Inhibition in Astrocytes Exposed to Oxygen and Glucose Deprivation

Recent studies have implicated the role of autophagy in brain ischemia pathophysiology. However, it remains unclear whether autophagy activation is protective or detrimental to astrocytes undergoing ischemic stress. This study evaluated the influence of ischemia-induced autophagy on cell death and the course of intrinsic and extrinsic apoptosis in primary cultures of rat cortical astrocytes exposed to combined oxygen-glucose deprivation (OGD). The role of autophagy was assessed by pharmacological inhibition with 3-methyladenine (3-MA). Cell viability was evaluated by measuring LDH release and through the use of the alamarBlue Assay. Apoptosis and necrosis were determined by fluorescence microscopy after Hoechst 33,342 and propidium iodide staining, respectively. The levels of apoptosis-related proteins were analyzed by immunoblotting. The downregulation of autophagy during OGD resulted in decreased cell viability and time-dependent changes in levels of apoptosis and necrosis. After short-term OGD (1, 4 h), cells treated with 3-MA showed higher level of cleaved caspase 3 compared with control cells. This result was consistent with an evaluation of apoptotic cell number by fluorescence microscopy. However, after prolonged exposure to OGD (8, 24 h), the number of apoptotic astrocytes (microscopically evaluated) did not differ or was even lower (as marked by caspase 3) in the presence of the autophagy inhibitor in comparison to the control. A higher level of necrosis was observed in 3-MA-treated cells compared to non-treated cells after 24 h OGD. The downregulation of autophagy caused time-dependent changes in both extrinsic (cleaved caspase 8, TNFα) and intrinsic (cleaved caspase 9) apoptotic pathways. Our results strongly indicate that the activation of autophagy in astrocytes undergoing ischemic stress is an adaptive mechanism, which allows for longer cell survival by delaying the initiation of apoptosis and necrosis.     

Programmed cell death in spinal cord injury pathogenesis and therapy

Spinal cord injury (SCI) always leads to functional deterioration due to a series of processes including cell death. In recent years, programmed cell death (PCD) is considered to be a critical process after SCI, and various forms of PCD were discovered in recent years, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis. Unlike necrosis, PCD is known as an active cell death mediated by a cascade of gene expression events, and it is crucial for elimination unnecessary and damaged cells, as well as a defence mechanism. Therefore, it would be meaningful to characterize the roles of PCD to not only enhance our understanding of the pathophysiological processes, but also improve functional recovery after SCI. This review will summarize and explore the most recent advances on how apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis are involved in SCI. This review can help us to understand the various functions of PCD in the pathological processes of SCI, and contribute to our novel understanding of SCI of unknown aetiology in the near future.     

The role of apoptosis in the pathogenesis of malignant melanoma

Malignant melanoma genesis is a very complex process that involves a sequence of pathogenetic cellular events. Mutation of various genes and numerous other cellular mechanisms play an important role in the course of malignant melanocyte alteration and their malignant transformation from naevi into melanoma. Apoptosis is an active, genetically controlled process of programmed cell death, which leads to cell destruction and cell death without involvement of surrounding cells or inflammatory response. In this process, disrupted mechanisms of cell regulation and apoptosis take place in malignant melanoma cells, thus leading to their uncontrolled proliferation and melanocyte growth. Apoptosis is a process that involves two major pathways, the intrinsic and extrinsic apoptotic pathway, which interlace at certain points and ultimately result in apoptosis. It can be said that molecular events regulating cell survival, normal growth arrest, apoptosis and cell differentiation, contribute to the overall pathogenesis of malignant cell growth. It is presumed that in the future, understanding of molecular aberrations and cellular processes, such as cell signaling, cell cycle regulation and cell apoptosis, will be essential for better patient monitoring and rational design of effective treatment.     

Mechanisms of non-apoptotic programmed cell death in diabetes and heart failure

Programmed cell elimination is an important pathological mediator of disease. Multiple pathways to programmed cell death have been delineated, including apoptosis, autophagy and programmed necrosis. Cross-talk between the signaling pathways mediating each process has made it difficult to define specific mechanisms of in vivo programmed cell death. For this reason, many “apoptotic” diseases may involve other death signaling pathways. Recent advances in genetic complementation using mouse knockout models are helping to dissect apoptotic and necrotic cell death in different pathological states. The current state of research in this area is reviewed, focusing upon new findings describing the role of programmed necrosis induced by the mitochondrial permeability transition in mouse models of heart failure and diabetes.Key words: apoptosis, necrosis, mitochondrial permeability transition pore     

AIF-Mediated Programmed Necrosis: A Highly Orchestrated Way to Die

Historically, two main forms of cell death have been distinguished: apoptosis and necrosis. Apoptosis was initially considered as the only physiological and programmed form of cell death. This type of death is recurrently associated with caspases, a family of cysteine proteases activated in apoptotic conditions. However, it is now widely recognized that programmed cell death (PCD) can also occur in the complete absence of caspase activation. The existence of non-caspase PCD pathways was corroborated by the discovery of caspase-independent executioners, such as the mitochondrial protein Apoptosis-Inducing Factor (AIF). Necrosis has often been viewed as an accidental and uncontrolled cell death process. Nevertheless, increasing evidence shows that, like apoptosis, necrosis could be a highly regulated type of PCD. Indeed, apoptosis and necrosis present more similarities than it has been originally thought. Here, we summarize the different classifications of PCD and the current knowledge of a necrotic PCD pathway mediated by AIF: alkylating DNA-damage mediated death. We also outline the molecular mechanisms controlling this form of PCD and discuss their potential relevance in physiological and pathological settings. These emerging data on the molecular mechanisms regulating programmed necrosis may certainly have potent therapeutic consequences in treating both apoptotic-resistant tumors and degenerating adult neurons.