Life On The Edge Alterations In The Apoptotic Machinery In Cancer Cells

Changes that disable the apoptotic machinery are now considered one of the hallmarks of neoplastic transformation (230-234). How inhibition of apoptosis contributes to neoplastic transformation is perhaps best understood for the oncoprotein myc, a transcription factor that is upregulated in proliferating cells but cannot induce neoplastic transformation unless an antiapoptotic Bcl-2 family member is also overexpressed (75,235,236). When cells are cultured under favorable conditions, myc overexpression drives proliferation, but when cells encounter unfavorable growth conditions, myc overexpression causes apoptosis (237,238). This myc-induced apoptosis appears to result from several distinct proapoptotic changes, including upregulation of p19ARF, which binds Mdm2 and allows upregulation of p53-dependent apoptotic mediators (239), upregulation of Bim (240), and downregulation of Bcl-2 and Bcl-xL (241). These proapoptotic changes must be overcome if cells are to be successfully transformed by myc. According to current understanding, other proliferation-inducing oncogenes likewise require the cooperation of antiapoptotic changes (233).

Because transforming oncogenes activate the intrinsic apoptotic pathway when cells encounter unfavorable growth conditions (242,243), it is perhaps not surprising that the intrinsic pathway is inhibited in a number of different ways in various cancers (233-245). Antiapoptotic Bcl-2 family members are overexpressed in some cancers (15,246,247). In others, constitutive activation of the mitogen-activated kinase pathway (139) induces activation (Bcl-2) or stabilization (Mcl-1) of group I Bcl-2 family members (see Section 7). In leukemia cell lines (248) and a substantial portion of mismatch repair-deficient colon and gastric cancers (249), the BAX gene is mutated, although the heterozygous nature of these mutations in clinical cancer (249) stands in contrast to results obtained in animal models (250) and by itself fails to completely account for any apoptotic defect. In other tumors, changes that upregulate the Akt pathway (251), including autocrine or paracrine activation of receptor tyrosine kinases, PI3KINASE gene mutation (252) or amplification (253), PTEN deletion, or AKT2 gene amplification (254), inhibit mitochondrial cytochrome c release (255).

The most common change that impinges on the mitochondrial pathway is mutation or deletion of the tumor suppressor p53, a transcription factor that is widely reported to induce apoptosis upon forced overexpression (256,257). Although many intrinsic pathway components, including Bax, Apaf-1, Bid, and caspase-6, have been identified as p53 transcriptional targets (256-258), gene-targeting studies have identified the BH3-only polypeptides Puma and, to a lesser extent, Noxa, as the most important contributors to p53-induced apoptosis (105-107). It currently appears that Puma plays a predominant role in p53-induced apoptosis after certain DNA-damaging stimuli (106), but further study is required to determine whether similar results are obtained after all types of DNA damage and in all cell types.

Despite the frequency of p53 mutations in clinical cancer, there is reason to question whether these lesions arise to counterbalance the proapoptotic effects of oncogenes early in carcinogenesis. Current evidence suggests that p53 mutations play an important role in vivo to counter the proapoptotic effects of myc overexpression in Burkitt's lymphoma-like B-cell neoplasms in mice (239). In epithelial neoplasms, however, p53 mutations are a late occurrence (259,260), raising the possibility that other antiapoptotic changes like those involving the PI3 kinase/Akt pathway (251,261), which often occur in atypia and carcinoma in situ, might play a more important role early in tumorigenesis.

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