Mechanizmy działania i strategie oporności komórek nowotworowych przeciwko apoptozie indukowanej przez TRAIL

Abstract

TRAIL (TNF-related apoptosis inducing ligand), a protein belonging to the tumor necrosis factor family, causes apoptosis induction through activation of its cognate death receptors (DR4, DR5). Binding TRAIL leads to induction of extrinsic or, in some cell types, intrinsic apoptosis pathways. Because of the lower death receptors surface expression on non-transformed cells than on cancer cells, DR4 and DR5 ligands attract a lot of attention as potential anti-cancer drugs. Despite exhibiting high activity in preclinical in vitro and in vivo models, in clinical trials TRAIL treatment proved to be inefficient. Lack of apoptotic activity is caused by intrinsic or secondary resistance to TRAIL, that is observed in cancer cells. Herein, we systematically review the resistance mechanisms to death-receptor triggered apoptosis. Identification of such mechanisms in clinical setting might serve as a “negative” biomarker, excluding patients unlikely to benefit from TRAIL-based therapies or present a possibility of pharmacological modulation.