Caspases and cancer: mechanisms of inactivation and new treatment modalities.

Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis. Deregulation of apoptotic signaling pathways may contribute to oncogenesis. Aspartate specific cysteine proteases, termed caspases are the key effector molecules in apoptosis. The aim of this review is to summarize the various defects in caspase-dependent cell death machinery identified in the neoplastic cells. These include not only mutations, but also alterations of gene methylation, and altered mRNA stability. Among the molecules that we discuss are elements of the extrinsic death pathway like CD95 (APO-1/Fas), FADD, FLIPs, FLICE, other apical caspases, components of the intrinsic apoptotic pathway like Apaf-1, caspase-9, and modulators of apoptotic pathways like IAPs, Smac/DIABLO, OMI/HtrA2, and other apoptosis regulating proteins. We also discuss recent data on cancer-specific agents that target effector mechanisms of apoptosis. Particular emphasis is given to the prospects for combining cell suicide-activating approaches with classical cancer therapies.