Research progress on the dual regulation of c-FLIP in apoptosis and proliferation and the relationship between c-FLIP and tumor prognosis, chemotherapy, and TRAIL treatment in cancers / 中国肿瘤临床

ABSTRACT

Cellular Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) belongs to the death effector domain superfamily, which is important in regulating apoptosis and proliferation. c-FLIP inhibits the extrinsic recep-tor-mediated apoptotic pathways and intrinsic mitochondrial apoptotic pathways through competition with caspase-8 for recruitment to Fas-associated death domain protein. Moreover, the cleavage products (i.e., p43-FLIP fragment and p22-FLIP fragment) directly acti-vate NF-κΒ, Erk survival signaling, and other non-apoptotic signaling pathways. The c-FLIP (L) can function either as an anti-apoptotic molecule, in a way analogous to c-FLIP (S) and c-FLIP (R), or as a pro-apoptotic molecule to facilitate the activation of caspase-8 at the death-induced signaling complex. The identified dual functionality of c-FLIP depends on various factors, including its expression level, interaction with caspase-8, and its subcellular localization. c-FLIP is frequently over-expressed in many different tumor types, and con-tributes to tumor cell immune surveillance, chemotherapy resistance, and apoptosis-resistance induced by TNFα, TRAIL, and FasL. Fur-thermore, c-FLIP is essential in obtaining aggressive biological behaviors, and is useful in predicting the prognosis of patients with vari-ous malignant tumors. This review focuses on the molecular mechanisms that control the dual regulation of c-FLIP in life/death deci-sion at death-induced signaling complex. Increasing evidence supports the function of c-FLIP as a tumor therapeutic marker to restore an apoptotic response for TRAIL therapy in cancers. Insight into these processes will improve our understanding of apoptosis, and pro-vide new approaches for rational treatment strategies.