Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells
Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells
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DOI：
10.1158/1535-7163.mct-07-2183
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
Wang, Xia;Chen, Wenshu;Lin, Yong
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）具有选择性杀伤转化细胞的作用，是一种潜在的抗癌药物。然而，TRAIL也可以刺激TRAIL耐药癌细胞的增殖和转移。因此，在TRAIL治疗期间获得的TRAIL抗性将使患者的治疗从有益转变为有害。在这项研究中，我们专注于获得性TRAIL耐药机制，并表明抗凋亡因子细胞FLICE样抑制蛋白（c-FLIP）和促生存Bcl-2家族成员髓样细胞白血病-1（Mcl-1）的表达升高是肺癌细胞中这种类型的TRAIL耐药的主要机制。长期暴露于肿瘤坏死因子相关凋亡配体（TRAIL）导致肺癌细胞对肿瘤坏死因子相关凋亡配体（TRAIL）诱导的细胞毒性产生抵抗，这种抵抗与c-FLIPL和Mcl-1（L）细胞水平的增加有关。c-FLIPL的过度表达抑制了caspase-8向死亡诱导信号复合物的募集，而Mcl-1（L）表达的增加则减弱了线粒体凋亡途径。c-FLIPL和Mcl-1（L）表达的升高是由于Akt介导的这些蛋白在TRAIL抗性细胞中的稳定化。重要的是，通过RNA干扰抑制c-FLIPL和Mcl-1（L）表达共同减轻了获得性TRAIL抗性。综上所述，这些结果鉴定了c-FLIPL和Mcl-1（L）作为获得性TRAIL耐药的主要决定因素，并且可以作为提高TRAIL对肺癌的治疗价值的分子靶点。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent due to its selectivity in killing transformed cells. However, TRAIL can also stimulate the proliferation and metastasis of TRAIL-resistant cancer cells. Thus, acquired TRAIL resistance during TRAIL therapy would shift the patient's treatment from beneficial to detrimental. In this study, we focused on the acquired TRAIL resistance mechanism and showed that the elevated expression of the antiapoptotic factor cellular FLICE-like inhibitory protein (c-FLIP) and the prosurvival Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) underlie the main mechanism of this type of TRAIL resistance in lung cancer cells. Chronic exposure to TRAIL resulted in lung cancer cell resistance to TRAIL-induced cytotoxicity, and this resistance was associated with the increase in the cellular levels of c-FLIPL and Mcl-1(L). Overexpresssion of c-FLIPL suppressed recruitment of caspase-8 to the death-inducing signaling complex, whereas increased Mcl-1(L) expression blunted the mitochondrial apoptosis pathway. The elevation of c-FLIPL and Mcl-1(L) expression was due to Akt-mediated stabilization of these proteins in TRAIL-resistant cells. Importantly, suppressing c-FLIPL and Mcl-1(L) expression by RNA interference collectively alleviated acquired TRAIL resistance. Taken together, these results identify c-FLIPL and Mcl-1(L) as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer.