c-FLIP在凋亡增殖中的双向调节作用及与肿瘤预后和治疗关系的研究

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

细胞型Fas相关死亡域样白介素-1β转换酶抑制蛋白(c-FLIP)在细胞凋亡和增殖信号通路中具有重要的调节作用。一方面通过与Caspase-8竞争性结合上游信号阻断凋亡通路,另一方面经酶切释放出p43-FLIP和p22-FLIP片段促进NF-κΒ、Erk等增殖信号通路,最终引发肿瘤发生发展、浸润转移。c-FLIP的双向调节作用与蛋白表达量、底物的亲和力和亚细胞定位密切相关。恶性肿瘤中c-FLIP高表达使细胞逃逸机体免疫监视、耐受化疗药物杀伤以及抵抗TRAIL、FasL诱导的凋亡。本文初步阐释c-FLIP在不同的细胞微环境中对凋亡-增殖通路的双向调节作用及其分子机制,并对c-FLIP与恶性肿瘤预后、化疗和TRAIL生物治疗相关性进行综述,为肿瘤化疗耐药和TRAIL抵抗提供理论基础。

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.