This review presents background on the signaling pathways involved in the different cell death outcomes. A re-examination of what we know about chemotherapy-induced death is vitally important in light of new understanding of nonapoptotic cell death signaling pathways. If we can precisely activate or inhibit molecules that mediate the diversity of cell death outcomes, perhaps we can succeed in more effective and less toxic chemotherapeutic regimens.
Strategically targeted cancer therapies are emerging from enormous efforts spent investigating basic signaling mechanisms involved in cell growth and cell death pathways. Many of the novel small molecules and biological agents being developed target pathways involved in apoptosis. Uncovering the molecular events that control and mediate apoptotic death has been fascinating and encouraged by the wealth of reagents and assays that offer specificity in detection.
Examination of other modes of cell death has lagged behind, in part because of the difficulty in their measurement. It is often stated as fact that chemotherapies induce death solely through apoptotic mechanisms.
Accumulating evidence suggests that tumor cell response to chemotherapy is not confined to apoptosis but also includes other modes of death [ 1 ]. In the first section of this review, we present discussions of the current knowledge of mechanistically described cell death outcomes, with an emphasis on their role in tumorigenesis and response to chemotherapy. In the second section, we examine the status of novel chemotherapeutic agents that target molecules involved in signaling of different cell death pathways.
Four categories of dynamic cellular activities that lead to cell death have been described: apoptosis, autophagy, necrosis, and mitotic catastrophe [ 2 ]. Permanent growth arrest, known as senescence, is also considered a type of cell death in the context of cancer therapy [ 3 ]. Programmed cell death results in the disintegration of cellular components and their engulfment by surrounding cells. Tissue remolding events during normal development of multicellular eukaryotic organisms rely on programmed cell death to help form the adult species.
They also operate in adult organisms to maintain normal cellular tissue. Necrosis and mitotic catastrophe are generally considered passive responses to massive cellular insult. However, new findings suggest that these forms of death may also be genetically controlled [ 6 — 8 ]. Senescence is an essential process of aging and occurs following a gene-directed program involving the erosion of telomeres and the activation of tumor suppression signaling pathways [ 9 ]. Dysregulation of the signaling pathways that control each of these forms of cell death has been implicated in tumorigenesis.
Other models of cell death have been described, including caspase-independent apoptosis, necroptosis, paraptosis, pyroptosis, and slow cell death, whose morphologic and biochemical characteristics vary from current definitions of the major cell death pathways described above [ 10 — 13 ]. In an attempt to simplify this discussion, only the five best-described cell death outcomes apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence are presented herein. It is also worth noting that a recent effort put forth by the editors of Cell Death and Differentiation has proposed to characterize cell death strictly in the precise terms of the parameters used to measure it and not in general terms that describe the presumed cell death pathway involved [ 14 ].
They also noted that apoptosis was responsible for maintaining tissue homeostasis by mediating the equilibrium between cell proliferation and death.
Programmed Cell Death, The Biology and Therapeutic Implications of Cell Death, Part B. Roya Khosravi-Far, Zahra Zakeri, Richard A. Lockshin and Mauro. The process of programmed cell death, or apoptosis, is generally to modulate the life or death of a cell is recognized for its immense therapeutic potential. . by necrosis or apoptosis depends in part on the nature of the cell death signal, . and regulation of cytotoxic Type 1 helper cells whereas granzyme B has no effect .
Morphologic characteristics of apoptosis include cell membrane blebbing, cell shrinkage, chromatin condensation, and nucleosomal fragmentation. Apoptosis has been considered a major mechanism of chemotherapy-induced cell death, and pathways regulating apoptosis are the focus of many preclinical drug discovery investigations.
There are two distinct molecular signaling pathways that lead to apoptotic cell death: a the intrinsic , or mitochondria-mediated pathway, and b the extrinsic , or extracellular activated pathway [ 4 , 16 , 17 ]. The intrinsic pathway is usually activated in response to intracellular stress signals, which include DNA damage and high levels of reactive oxygen species ROS , as well as by viral infection and activation of oncogenes. The extrinsic pathway is triggered by the binding of an extracellular ligand to a receptor on the plasma membrane.
Both pathways activate proteolytic enzymes called caspases that mediate the rapid dismantling of cellular organelles and architecture. Caspases are a family of proteins containing a nucleophilic cysteine residue that participates in the cleavage of aspartic acid—containing motifs [ 18 ].
Caspases are expressed as inactive precursors that form active oligomers after initiating cleavage events. Evidence suggests that initiator caspases are capable of autocatalytic activation while effector caspases need activation by initiator caspase cleavage. Bcl-2 family members act by regulating the efflux of apoptogenic proteins from mitochondria. Bcl-2 proteins contain from one to four Bcl-2 homology BH domains.
The number and combination of the BH domains dictate whether the proteins are proapoptotic or antiapoptotic. In mouse cells, deletion of Bax and Bak is sufficient to prevent mitochondrial outer membrane permeabilization MOMP induced by upstream apoptotic events [ 19 , 20 ]. Bax and Bak normally exist as inactive monomers.
grupoavigase.com/includes/423/2819-donde-conocer-gente.php Bax resides in the cytosol or loosely attached to intracellular membranes [ 21 ], and Bak is bound by Mcl-1, Bcl-xL, or voltage-dependent anion channel protein 2 VDAC-2 in the mitochondrial outer membrane [ 22 , 23 ]. Once released, cytochrome c binds apoptotic protease-activating factor 1 Apaf-1 , which recruits pro-caspase-9, promoting its self-activation. Activated caspase-9 cleaves the downstream effectors caspase-3 and caspase-7, which rapidly cleave intracellular substrates. The BH3-only proteins are universally proapoptotic, and each can act either to antagonize antiapoptotic members or activate proapoptotic members.
BH3-only proteins need to be activated in order to elicit their death signal. The proapoptotic activity of BH3-only proteins appears to be kept in check by either transcriptional control mainly by p53 or post-translational events. For example, cellular stresses, such as ionizing radiation IR or chemotherapy, activate a DNA damage response that stabilizes the p53 tumor suppressor protein. Another role for p53 has been identified showing that p53 acts directly to increase MOMP by binding Bcl-2 family members and helping mediate Bax and Bak dimerization [ 28 , 29 ]. The extrinsic pathway is activated by members of two protein families, the tumor necrosis factor TNF family and the receptors for these ligands TNFR [ 30 ].
Most TNF family members bind receptors that activate signals involved in proinflammatory responses and do not signal cell death. After extracellular ligand binding, the cytoplasmic end of the TNFR recruits initiating caspases. The BH3-only protein Bid connects the extrinsic pathway to mitochondria. Bid is cleaved by caspase-8, resulting in its myristyolization of a newly-exposed glycine residue to form tBid. Apoptotic cell death is as a key element in maintaining immune homeostasis and preventing the emergence of lymphomas or the development of autoimmunity [ 41 ].
Cytotoxic immune cells can also induce apoptosis through exocytosis of specialized granules that contain perforin and caspase-like proteases, called granzymes [ 47 ]. Entry of these proteins into target cells activates apoptosis, through both caspase-dependent and independent mechanisms. While apoptosis is increasingly well defined at the molecular level, necrosis has been lacking a molecular signature and has been referred to as a form of cell death that is uncontrolled and pathological.
However, recent studies suggest that necrosis is a regulated event that may be involved in multiple developmental, physiological, and pathological scenarios [ 7 , 48 , 49 ]. Unlike apoptosis, in which the Bcl-2 family of proteins and caspases play key roles, necrosis is induced by inhibition of cellular energy production, imbalance of intracellular calcium flux, generation of ROS, and activation of nonapoptotic proteases. These events often potentiate each other and synergize to cause necrosis. Cells can generate ATP through oxidative phosphorylation or glycolysis. Glycolysis occurs in the cytosol, while oxidative phosphorylation occurs in the mitochondrial matrix.
ATP depletion results in loss of cellular function and necrosis. Uncoupling the electron transport chain disrupts ATP production, resulting in the depolarization of the mitochondrial inner membrane, referred to as mPT [ 50 , 51 ]. Although mPT has been proposed to mediate apoptosis by inducing the release of mitochondrial apoptogenic factors, persistent opening of the PT pore leads to necrosis [ 52 — 54 ]. Highly proliferative cells are dependent on glycolysis for energy production, and if glycolysis is inhibited, cellular ATP levels can dramatically decline.
Cells in an aerobic environment are constantly generating ROS. While physiologic levels of ROS can serve as signaling molecules to regulate transcription, excessive production of ROS leads to oxidative stress, damage of intracellular molecules and organelles, and ultimately necrosis. ROS also modify lipids at the multiple double bonds in polyunsaturated fatty acids. Unlike apoptosis and necrosis, autophagy is not synonymous with cell death. Autophagy is evolutionarily conserved and occurs in all eukaryotic cells, from yeast to mammals [ 66 ].
Autophagy is activated in response to nutrient starvation, differentiation, and developmental triggers. It is an adaptive process responding to metabolic stresses that results in degradation of intracellular proteins and organelles [ 5 , 67 ]. During autophagy, portions of the cytoplasm are encapsulated in a double-membrane structure referred to as an autophagosome.
Autophagosomes then fuse with lysosomes where the contents are delivered, resulting in their degradation by lysosomal hydrolases. Under normal physiological conditions, autophagy occurs at basal levels in most tissues, contributing to the routine turnover of cytoplasmic components. It can promote cell adaptation and survival during stresses such as starvation, but under some conditions cells undergo death by excessive autophagy. In yeast, a cassette of autophagy-related genes referred to as ATG have been identified that regulate autophagy induction, autophagosome formation and expansion, fusion with lysosomes, and the recycling of autophagosome contents [ 66 ].
Some of the mammalian orthologs to these genes have been identified. Studies involving Beclin 1 , the mammalian ortholog of yeast Atg6 , gave the first indications linking dysfunctional autophagy with tumorigenesis. Beclin 1 is required for autophagosome formation and has been suggested to be a haploinsufficient tumor suppressor gene. Several lines of evidence have found that a cross-talk exists between autophagic and apoptotic pathways.
Beclin 1 was originally identified through its interaction with Bcl-2 [ 71 ]. Recent findings have shown that Bcl-2 and Bcl-xL expression can sensitize cells to autophagic death induced by etoposide [ 72 ], and that Bcl-2 inhibits Beclin 1-mediated autophagy in response to starvation [ 73 ].
These contradictory findings suggest that the outcome of the autophagic response may vary depending on the type of insult or cellular stress. Mitotic catastrophe is a process involving aberrant mitosis resulting from improper segregation of chromosomes during sister chromatid separation. Generally, it is not considered a form of death, but rather an irreversible trigger for death [ 74 ]. Eukaryotic cells have complex surveillance mechanisms that monitor the structure of chromosomes and activate multiple signaling pathways after detecting DNA damage.