Apoptosis

Apoptosis is the mechanism that orchestrates programed cell death when a cell cannot overcome certain type of insults coming from its environement. Apoptosis is a multistep process involving many proteins, and also the participation of the mitochondria. The resulting apoptotic phenotype is characterized by cell shrinking, condensed chromatin with nuclear margination and DNA fragmentation, and membrane blebbing.

7.01.5.3.1 Intrinsic and extrinsic apoptosis pathways

Originally thought to be exclusively devoted to energy production, the role of mitochondria was recently revisited as these organelles actively participate in the intrinsic (or stress-induced) apoptosis machinery (Figure 3). Upon activation of apoptotic stimuli (e.g., p53 stabilization), proapoptotic members of the Bcl-2 superfamily proteins such as Bax or Bak can translocate into the membrane of the mitochondria. They are thought to disrupt the outer membrane of mitochondria, thereby leading to the release of proapoptotic mediators (cytochrome-c, Sma/Diablo, Omi/HtrA2, endonuclease G, flavoprotein AIF), normally located in the mitochondria, into the cytosol. This chain of events, termed mitochondrial membrane permeabilization, is nonreversible and is considered to be the apoptosis checkpoint.135 The exact mechanism by which Bax/Bak induces mitochondrial membrane permeabilization is still highly controversial, but it has been shown that Bax oligomers can form in liposomes pores that are large enough for cytochrome-c release.136 Released cytochrome-c, interacts with Apaf-1 and the resulting complex (the apoptosome complex), will lead to the maturation of zymogen procaspase 9 to active caspase 9, which in turn will activate the executioner procaspases 3, 6, and 7 into their active forms.137

In parallel to the intrinsic pathway, the extrinsic apoptosis pathway (Figure 3) is activated upon ligands tumor necrosis factor-alpha (TNF-a), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL) binding to their cognate membrane-bound receptors of the tumor necrosis family (TNF) super family of receptor proteins (death receptors TNFR-I and TNFR-II, Fas, and DR4/5). Activation of the receptors leads to the maturation of procaspases 8 and 10 which will then activate the executioner caspases 3, 6, and 7, without any participation of the mitochondria.

7.01.5.3.2 Defects of the apoptosis machinery in cancer cells

Cancer cells exhibit enhanced glycolytic ATP generation and decreased respiratory phosphorylation, even under normal oxygen tension (the Warburg effect). This metabolic alteration might be linked to a change in the composition or the regulation of the mitrochondria organization, which would prevent or reduce mitochondrial apoptosis. Indeed, mitochondra with resistance to mitochondrial membrane permeabilization have been observed in leukemia cell lines.138

Intrinsic pathway Extrinsic pathway

Chemotherapy

Figure 3 The apoptosis machinery. The different players involved in either intrinsic or extrinsic apoptosis cascades discussed in the text are shown in this simplified scheme.

Antiapoptotic members of the Bcl-2 superfamily all presumably have oncogenic potential due to their ability to block cytochrome-c release. This is indeed the case for Bcl-2 itself and for Bcl-xL. The Bcl-2 gene is often translocated in human follicular lymphoma, where it is constitutively expressed.139 It is now well accepted that high levels of Bcl2 or Bcl-xL may impede the oligomerization of the proapoptotic members.140 However, in transgenic mouse models mimicking the Bcl-2 translocation, spontaneous lymphomas take many months to develop, and the penetrance of the disease is rather low, suggesting that Bcl-2 overexpression on its own is not highly oncogenic and that progression of malignancy requires synergistic mutations. The oncogenic potential of Bcl-2 is more effective when the Myc oncogene is coexpressed, either in vitro or in vivo. Consistent with this, lymphoid malignancies with elevated Bcl-2 expression also contains Myc translocation141 and p53 mutations.142

In contrast to Bcl-2-like proteins, proapoptotic members could be considered to be tumor suppressor proteins. Since Bax and Bak have redundant functions, tumor promotion would require inactivation of both genes. Some human colorectal and hematopoietic tumors exhibit mutations in the Bax or Bak genes. Reduced expression of the Bax proapoptotic protein has also been reported in colorectal carcinoma, and there is often a good correlation between the expression levels of the various Bcl-2 members and clinical outcome.143

Human tumor cells may be defective in the assembly of the apoptosome. This is often the result of a loss of expression of the Apaf-1 protein, as observed in melanomas, leukemias, glioblastoma, and ovarian cancers. Apoptosome assembly may also be blocked by the overexpression of certain chaperones or oncogenes.144 Thus, hsp70 overexpression in breast cancer is correlated with a shorter disease-free survival interval, increased frequency of metastasis, and decreased responsiveness to chemotherapy.145 Expression of the ProToncogene suppresses apotosome formation,146 and increased ProTexpression have been found in human malignancies including lung, hepatocellular, breast, and colon cancers.

Finally, caspase activation is a step in the apoptosis pathway that could be blocked by direct interaction with the inhibitors of apoptosis (IAPs). From the IAPs family members (NAIP, c-AIP1, c-IAP2, XIAP, survivin, livin, ILP-2, c-FLIPL, ARC, and BAR), survivin appears to have the most clinically relavant link to cancer, as this protein has been shown to be overexpressed uniquely in cancer cells but not in the normal surrounding tissues.147 A correlation has been established between survivin overexpression and poor prognosis for a wide variety of tumor types.148 XIAP and ML-IAP are also overexpressed in acute myelogenous leukemia and melanoma, respectively.

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