Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1
Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1
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DOI：
10.1016/j.bbrc.2016.12.037
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发表时间：
2017-01-22
影响因子：
3.1
通讯作者：
Tanaka, Nobuyuki
中科院分区：
文献类型：
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作者：
Suzuki, Junya;Nakajima, Wataru;Tanaka, Nobuyuki
自噬是一种动态循环系统，利用溶酶体蛋白分解产生新的蛋白质和能量，用于细胞更新和动态平衡。虽然巨自噬被认为是许多癌细胞的生存途径，但伴侣介导的自噬(CMA)是一种选择性的蛋白质降解系统，在癌症中的作用尚不完全清楚。在这里，我们证明了溶酶体蛋白分解，而不是巨噬，减弱了酪氨酸激酶抑制剂Crizotinib诱导的非小细胞肺癌(NSCLC)细胞系EBC1的凋亡。在EBC1细胞中，Crizotinib诱导BIM依赖的细胞凋亡，这种凋亡通过抑制溶酶体蛋白降解而增强。此外，泛素-蛋白酶体系统通过抑制溶酶体蛋白分解和抑制CMA介导物HSC70(热休克相关蛋白70 kDa)和LAMP2A(溶酶体膜蛋白2A型)的表达而诱导促生存蛋白MCL1的降解，这表明在癌细胞中存在CMAM介导的MCL1稳定系统。事实上，在几个非小细胞肺癌细胞系中也观察到了相同的mcl1稳定系统；在这些细胞中，它们的特异性分子靶向药物或bcl2和bclX-L的特异性抑制剂abt-263(Navitoclax)，而不是mcl1的特异性抑制剂，联合CmA抑制有效地诱导了细胞凋亡。因此，我们的结果表明CMA稳定MCL1在肺癌中的作用是一种新的机制，并可能成为一种有效的肺癌联合化疗方法。(C)2016 Elsevier Inc.保留所有权利。
Autophagy is a. dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1. In EBC1 cells, crizotinib induced BIM-dependent apoptosis, which was enhanced by inhibition of lysosomal proteolysis. Moreover, degradation of the pro-survival protein, MCL1, by the ubiquitin-proteasome system was induced by inhibition of lysosomal proteolysis, and by inhibition of the expression of the CMA mediators, HSC70 (heat shock cognate protein 70 kDa) and LAMP2A (lysosome membrane protein type 2A), suggesting the existence of a CMAmediated MCL1 stabilization system in cancer cells. Indeed, the same MCL1 stabilization system was also observed in several NSCLC cell lines; in these cells, their specific molecular-targeted drug or ABT-263 (Navitoclax), the specific inhibitor of BCL-2 and BCL-X-L, but not of MCL1, effectively induced apoptosis in combination with CMA inhibition. Therefore, our results indicate a novel mechanism of MCL1 stabilization in lung cancers by CMA, and a candidate efficient combination chemotherapy method against lung cancers. (C) 2016 Elsevier Inc. All rights reserved.