Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation
Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation
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DOI：
10.1016/j.molonc.2013.07.010
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发表时间：
2013-12-01
影响因子：
6.6
通讯作者：
Friese, Klaus
中科院分区：
文献类型：
--
作者：
Bruening, Ansgar;Rahmeh, Martina;Friese, Klaus
内质网（ER）应激和自噬是两种基本的细胞生存机制，经常同时发生。化疗药物故意诱导的癌细胞中广泛的ER应激可能导致生长停滞和细胞死亡。然而，ER应激和自噬之间的联系还没有很好地理解。在这项研究中，用ER应激诱导药物奈非那韦治疗癌细胞导致内源性mTOR抑制剂sestrin-2（SESN 2）的表达。SESN 2表达的上调与ER应激标志物ATF 4、ATF 3和CHOP的表达相关。SESN 2上调也发生在用蛋白酶体抑制剂硼替佐米处理的细胞中。ATF 4而非ATF 3或CHOP的异位表达引起SESN 2表达的转录上调，表明ATF 4对SESN 2的表达调控。异位SESN 2的瞬时过表达导致mTOR抑制和自噬，证实了ER应激、SESN 2上调和mTOR抑制之间的联系。因此，用ER应激诱导剂奈非那韦处理的癌细胞显示出mTOR活性降低以及相关的ATF 4和SESN 2表达水平增加。这些结果表明，ATF 4调节的SESN 2表达呈现了ER应激与mTOR抑制和自噬之间的新联系。nelfinavir对mTOR的抑制作用目前正在癌症患者的临床试验中，这也可以解释其在癌细胞中诱导自噬、生长停滞和放射增敏的观察能力。(C)2013年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Endoplasmic reticulum (ER) stress and autophagy are two basic cell survival mechanisms often occurring in concert. Extensive ER stress in cancer cells deliberately induced by chemotherapeutic drugs may lead to growth arrest and cell death. However, the link between ER stress and autophagy is not well understood. In this study, the treatment of cancer cells with ER stress-inducing drug nelfinavir resulted in the expression of endogenous mTOR inhibitor sestrin-2 (SESN2). Upregulation of SESN2 expression was associated with expression of ER stress markers ATF4, ATF3, and CHOP. SESN2 upregulation also occurred in cells treated with the proteasome inhibitor bortezomib. Ectopic expression of ATF4, but not of ATF3 or CHOP, caused transcriptional upregulation of SESN2 expression, indicating expressional regulation of SESN2 by ATF4. Transient overexpression of ectopic SESN2 resulted in mTOR inhibition and autophagy, confirming a link between ER stress, SESN2 upregulation, and mTOR inhibition. Accordingly, cancer cells treated with the ER stress-inducing agent nelfinavir showed reduced mTOR activity and associated increases in the expression levels of ATF4 and SESN2. These results show that ATF4-regulated SESN2 expression presents a new link between ER stress and mTOR inhibition and autophagy. mTOR inhibition by nelfinavir, which is currently in clinical trials for cancer patients, may also explain its observed ability to induce autophagy, growth arrest, and radiosensitization in cancer cells. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.