Apoptosis intrinsic death pathway

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Increased activity of GSK-3/3 has been reported during neuronal degeneration (Beurel and Jope, 2006) and it has been associated with the promotion of the intrinsic mitochondrial pathway of apoptosis (Brazil and Hemmings, 2001). Pharmacological inhibition of GSK-3/3 reduces neuronal cell death caused by cerebral ischemia (Kelly et al., 2004), suggesting that prevention of GSK-3/3 activation may represent a potential approach to minimize neurodegeneration in the retina. 

Mammalian cells contain machinery that permits them to quickly commit apoptosis, or programmed cell death, in response to physiological, pathogenic, or cytotoxic stimuli. Extensive evidence indicates that during apoptosis (intrinsic pathway). 

Figure 1. Schematic of the apoplotic signaling pathways. The intrinsic apoptotic pathway consists of the mitochondrial pathway. The extrinsic pathway mediates apoptosis through activation of the death receptors, TNF-o/Fas receptors. Apoptosis is executed by activation of proteases, known as caspascs. ATP is essential for apoptosis. Bel-2 family proteins are apoptosis regulating proteins Bcl-2 inhibits while Bid, Bax, Bad facilitate apoptosis. An interaction between these two apoptotic pathways exists. See text for a more detailed explanation.

Fig. 15.3 The major pathways of apoptosis. The extrinsic pathway uses extracellular death ligands (Fas ligand, tumor necrosis factor (TNF)) to activate death receptors which pass the apoptotic signal to initiator caspases (e. g. capsase 8) and to the executioner caspases (e. g. caspase 3 caspase 7). In the execution phase of apoptosis, various cellular substrates are degraded leading to cellular collapse. The intrinsic pathway uses the mitochondria as a central component for activation of apoptosis. In this pathway, a multitude of intracellular signals including various stresses, DNA damage and inappropriate cell signaling lead to activation of the pro-apoptotic protein Bax which induces release of cytochrome c from mitochindria, formation of the apoptosome and activation of the initiator caspase 9. Finally, the executioner caspases are activated and cells are destructed by proteolysis. Apoptosis via this pathway can be controlled by various antiapoptotic proteins including the Bcl-2 protein and inhibitors of apoptosis.

B-cell lymphoma 2 (Bcl-2) family members are regulators of the intrinsic apoptosis (programmed cell death) pathway, and anti-apoptotic family members have been strongly implicated in cancer [172]. Heterodimer-forming interactions between anti-apoptotic family members such as Bcl-xL or Bcl-2, and ot-helical domains of pro-apoptotic proteins control the ability of cells to carry out the apoptotic program. Several compounds have been reported to bind to and inhibit various anti-apoptotic Bcl-2 family members, but for most of these compounds reported affinities are poor, and structural information is unavailable [15]. 

Extensive literature has been dedicated to define the types of cell death, considering morphological and biochemical aspects [86, 87, 88], Induction of death of cancer cells by alterations of mitochondrial bioenergetics have been proposed as promising approach for synthetic and natural compoimd s [23], Mitochondria participate in different types of cellular death, specially apoptosis (intrinsic pathway), programmed necrosis and autophagy [15, 16, 89], which can be triggered by anti-cancer alkaloids. 

Su and coworkers investigated the induction of apoptosis by Tan-I at 1-10 pg/mL in human colon cancer Colo 205 cells. Tan-I reduced cell growth in a concentration-dependent manner, inducing apoptosis accompanied by an increase in TUNEL-stained cells in the sub-Gl fraction. The treatment with Tan-I at 0, 1, 2.5, 5, and 10 pg/mL for 72 h increased the percentage of cells in sub-Gl phase from 3.83% to 7.22%, 8.68%, 14.4%, and 32.98%, respectively. The expression of p53, p21, bax, and caspase-3 increased in Tan-I-treated cells. The authors suggested that Tan-I induces apoptosis in Colo 205 cells through both mitochondrial-mediated intrinsic ceU-death pathways and p21-mediated GO/Gl cell cycle arrest [50]. 

Fig. 41.2 Cellular location and schematic representation of the apoptotic pathways activated by Berberine in tumor cells. Upper panels, berberine accumulates in the nucleus of A549 lung carcinoma cell line. Cells were incubated with berberine (50 pM) for the indicated times and, subsequently, nuclei were stained with the fluorescent dye DRAQ5. Images were taken in a Leica TCS SP2 confocal microscope. Pictures correspond to the central section in a confocal z-stack acquired sequentially. Green berberine Red DRAQ5 Grey DIC image. Lower panel, berberine activates in vitro the intrinsic cell death pathway. Berberine-induced apoptosis is initiated after DNA damage by cell cycle arrest in GO/Gl mediated by the ATM/p53 pathway. In addition, berberine is able to block cell cycle in G2M by activation the ATM/Chkl p53-independent pathway in some tumor cell types. Activation of these pathways leads to transcription (TF) of...

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

Goyeneche AA, Harmon JM, Telleria CM (2006) Cell death induced by serum deprivation in luteal cells involves the intrinsic pathway of apoptosis. Reproduction 131 103-111 Gray MW, Burger G, Lang BF (2001) The origin and early evolution of mitochondria. Genome Biol 2 1018.1-1081.5... 

Caspase activation occurs as a late and common step in all cells undergoing apoptosis. Nevertheless, there are many initial pathways that can result in caspase activation. Probably, each distinct pathway is triggered by different apoptotic stimuli. In mammalian cells, the apoptotic response is usually mediated by the intrinsic and extrinsic pathways, depending on the origin of the death signal. The intrinsic pathway can further be divided into mitochondrial and ER stress pathways. 

Signaling for apoptosis can be initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway) [31, 32]. In both pathways, signaling results in the activation of initiator caspases. Active initiator caspases then sequentially activate downstream effector caspases such as caspase -3, -6, and -7. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair... 

The mechanisms of apoptosis are highly complex and sophisticated, involving an energy-dependent cascade of molecular events (Figure 16.11). There are two main apoptotic pathways the extrinsic or death receptor pathway and the intrinsic or... 

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