Oncogenic alterations in the extrinsic death pathway

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)


One of the hallmarks of cancer cells is their resistance to normal death pathways. Cancer cells adopt different mechanisms to escape apoptosis. For evading extrinsic apoptosis, oncogenic alterations in death receptors, adaptor proteins, initiator caspases, and the apoptosis regulators can occur.

Down-regulation of death-receptor signaling through silencing death-receptor genes or deficient transport of receptors to the cell surface is a common strategy for cancer cells to escape extrinsic apoptosis. For example, Fas expression levels are decreased in hepatoma, melanoma, and neoplastic colon epithelium (125–128). Decreased Fas expression is found to be associated with cancer progression and metastasis (128). A homozygous deletion of TRAIL-R1 is found in the human nasopharyngeal cancer cell line (129) and epigenetic silencing of TRAIL-R1 is found in ovarian cancer, glioblastoma, and melanoma (130–132). Deficient transport of TRAIL-R1 to cell surface in colon cancers causes resistance to TRAIL-induced apoptosis (133). Loss-of-function mutations have been identified in death receptors, abolishing their ability to induce apoptosis. For example, mutations in the Fas death domain have been identified in certain cancers to block recruitment of FADD (134–135). Loss-of-function mutations in TRAILR1 and TRAIL-R2 are also found in lung, breast, and head and neck cancers. These mutations are located primarily in the death domain and cause defects in transmitting the death signal (136–140).

Post-translational modification of death receptors appears important for promoting death signal transmission. Oglycosylation of TRAIL-R1/R2 is reported to facilitate TRAIL receptor clustering, which mediates higher-order complex formation and consequent caspase-8 activation (55). The mRNA level of the peptidyl O-glycosyltransferase GALNT14 is much lower in TRAIL-resistant cancer lines compared to the TRAIL-sensitive lines (55).

Upregulated decoy receptors compete with death receptors to bind death ligands, and thereby inhibit extrinsic apoptosis. DcR3 was found to be over-expressed in several types of tumor, such as lung, colon, breast, and rectum cancer (51,141–143). Expression levels of DcR3 also correlated with tumor malignancy; 15 of 18 grade IV glioblastomas showed significant DcR3 immunoreactivity, while 11 grade II astrocytomas showed no expression (144). Thus, tumor cells might acquire survival advantages by escaping FasLand TL1A-induced cell death. DcR3 is also reported to be a prognostic marker for lymph-node invasion in gastric cancer (145).

FADD is an important adaptor protein for DISC formation and is essential to activate initiator caspases and induce apoptosis. Defective regulation of FADD protein expression has been associated with cancer malignancy and poor prognosis (146). Mutations in the death domain of FADD which abolish biding of FADD to death receptors are rare, but have been found in colon and non-small-cell lung cancers (147).

Inactivation of caspase-8 is a potential mechanism to escape extrinsic apoptosis. Lack of caspase-8 expression is frequently identified in neuroendocrine cancers, but is rarely observed in epithelial-derived cancers (148). Dominant negative mutations that prevent recruitment of wild-type caspase-8 to the DISC have been identified in colon, gastric, and head and neck cancers at low frequency (149–151). The fact that caspase-8 expression is elevated in certain cancers could suggest a possible pro-tumorigenic role that is independent of its role in apoptosis (148). Alternatively, elevated caspase-8 levels could potentially reflect tolerance of caspase-8 due to up-regulation of caspase inhibitors or other pro-survival mechanisms. Recent studies found that pro-caspase-8 can be phosphorylated by Src, resulting in inhibition of proteolytic activation of caspase-8, and binding of caspase-8 to the p85 subunit of PI3K and Scr, to promote cell migration and invasion (152–154).

Although cFLIPL may have dual functions in normal cells, it behaves as a constitutive apoptosis inhibitor in cancer cells. Over-expression of cFLIPL has been observed in many tumor types (e.g. melanoma, pancreatic, prostate, lung, endometrial, colon cancer etc.) and its expression level is correlated with cancer progression and poor prognosis (72,155–156). Increased cFLIPL expression also causes cancer resistance to Fas, TRAIL, or chemotherapy-induced apoptosis (157–158). cFLIPL could also inhibit apoptosis in cancer cells by competitively binding to FADD to block caspase-8 activation. cFLIPL can also bind TRAF2 and RIP1 to form complexes that activate pro-survival NFB and ERK signaling pathways (155).

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