Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review

Figure 3 Different modalities of cell death. Unpredictable perturbations in the extracellular or intracellular microenvironments of a cell can activate several signal transduction cascades that ultimately lead to various forms of cell death. Type I cell death apoptosis: the extrinsic pathway of apoptosis is mediated by Fas-associated death domain protein (FADD). Caspase 8, in turn, triggers caspase 3 and 7, which then activates caspase 9. Both intrinsic and mitochondrial pathways of apoptosis are mediated through the inhibition of anti-apoptotic Bcl2, which in turn activates Bax/Bak and induces release of cytochrome c from the mitochondria. The activation of caspase 9 in the apoptosome induces apoptotic cell death. Type II cell death autophagy: autophagy is an active lysosomal degradative flux, which can be divided into three distinct types; macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy involves four different steps: initiation, autophagosome nucleation, phagosome expansion and completion, and autolysosome docking. The tightly-regulated autophagy machinery is mediated through several autophagy-related (Atg) molecules. Regulated necrosis/necroptosis: regulated necrosis is mediated through the interaction of receptor interacting protein 1 (RIP1) with RIP3 upon caspase 8 inhibition. RIP3 and mixed-lineage kinase domain-like (MLKL) are phosphorylated and assembled into complex IIb, which is then translocated to the plasma membrane to mediate membrane permeabilization. Ferroptosis: this regulated form of cell death is driven by the loss of glutathione peroxidase 4 (GPX4) activity, a lipid repair enzyme, followed by the accumulation of lipid hydroperoxides. Autosis: a plasma membrane Na+/K+-dependent autophagy form of cell death. Entosis: internalized cells undergo entotic cell death through the formation of entotic vacuoles, which is mediated by autophagy proteins like Vps34, etc. Pyroptosis: a caspase-dependent cell death mechanism that is an intermediary variation of apoptosis and necrosis. Caspase 1 is activated by the NLRP3 inflammasome, which activates the inflammatory cytokines interleukin 1β and interleukin 18, which in turn mediate the lytic cycle.