Safa A R
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Exp Oncol. 2012 Oct;34(3):176-84.
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator and resistance factor that suppresses tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, as well as apoptosis triggered by chemotherapy agents in malignant cells. c-FLIP is expressed as long (c-FLIP(L)), short (c-FLIP(S)), and c-FLIP(R) splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5) in a ligand-dependent and -independent fashion and forms an apoptosis inhibitory complex (AIC). This interaction in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP(L) and c-FLIP(S) are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-kB. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIP(L) in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIP(L) and c-FLIP(S) splice variants have been found, and much effort is focused on developing other c-FLIP-targeted cancer therapies. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, (2) the molecular mechanisms and factors that regulate c-FLIP expression, and (3) modulation of c-FLIP expression and function to eliminate cancer cells or increase the efficacy of anticancer agents. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".
细胞型FLICE（FADD样白介素-1β转换酶）抑制蛋白（c-FLIP）是一种主要的抗凋亡调节因子和耐药因子，可抑制肿瘤坏死因子-α（TNF-α）、Fas-L和肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡，以及恶性细胞中化疗药物引发的凋亡。c-FLIP在人类细胞中以长（c-FLIP(L)）、短（c-FLIP(S)）和c-FLIP(R)剪接变体的形式表达。c-FLIP以依赖配体和不依赖配体的方式与FADD和/或半胱天冬酶-8或-10以及TRAIL受体5（DR5）结合，并形成凋亡抑制复合物（AIC）。这种相互作用进而阻止死亡诱导信号复合物（DISC）的形成以及随后半胱天冬酶级联反应的激活。已知c-FLIP(L)和c-FLIP(S)在各种信号通路中也具有多功能作用，以及激活和/或上调包括Akt、ERK和NF-κB在内的多种细胞保护和促生存信号蛋白。在各种肿瘤类型中均发现c-FLIP表达上调，并且其沉默已被证明可恢复细胞因子和各种化疗药物引发的凋亡。因此，c-FLIP是癌症治疗的一个重要靶点。例如，在多种人类癌细胞系中特异性敲低c-FLIP(L)表达的小分子干扰RNA（siRNA）增强了TRAIL诱导的DISC募集，并提高了化疗药物的疗效，从而增强了效应半胱天冬酶的刺激和凋亡。此外，已发现可导致c-FLIP降解以及降低c-FLIP(L)和c-FLIP(S)剪接变体的mRNA和蛋白质水平的小分子，并且目前很多工作都集中在开发其他针对c-FLIP的癌症治疗方法上。本综述重点关注：（1）c-FLIP剪接变体在预防凋亡以及诱导细胞因子和化疗药物耐药方面的抗凋亡作用；（2）调节c-FLIP表达的分子机制和因素；（3）调节c-FLIP的表达和功能以消除癌细胞或提高抗癌药物的疗效。本文是名为“凋亡：四十年之后”的特刊的一部分。
