Evasion of apoptosis as a cellular stress response in cancer

Abstract

One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis can be part of a cellular stress response to ensure the cell's survival upon exposure to stressful stimuli. Apoptosis resistance may contribute to carcinogenesis, tumor progression, and also treatment resistance, since most current anticancer therapies including chemotherapy as well as radio- and immunotherapies primarily act by activating cell death pathways including apoptosis in cancer cells. Hence, a better understanding of the molecular mechanisms regarding how cellular stress stimuli trigger antiapoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death is expected to provide the basis for a rational approach to overcome apoptosis resistance mechanisms in cancers.

Figure 1

Interplay of cellular stress signals with apoptosis pathways. Signaling via the death receptor pathway can be inhibited by downregulation or epigenetic silencing of death receptors (DRs) or upregulation of cFLIP by hyperoxia. In the mitochondrial pathway, Bcl-2 favors a prooxidant milieu that promotes survival, while the reduced form of cytochrome c is inhibited in its activity to trigger caspase activation via the apoptosome. At the postmitochondrial level, translation of XIAP and cIAP1 is sustained via an IRES-dependent mechanism even under cellular stress conditions. See text for more details.