Drug-induced Myc-mediated apoptosis of cancer cells is inhibited by stress protein Hsp70
Drug-induced Myc-mediated apoptosis of cancer cells is inhibited by stress protein Hsp70
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DOI：
10.1002/ijc.22974
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发表时间：
2007-12-15
影响因子：
6.4
通讯作者：
Guzhova, Irina V.
中科院分区：
文献类型：
--
作者：
Afanasyeva, Elena A.;Komarova, Elena Yu.;Guzhova, Irina V.
Myc 癌蛋白具有刺激细胞生长和凋亡的双重功能。后者的功能通常在肿瘤发展过程中被消除。 Hsp70 应激蛋白是一种有效的抗凋亡分子，但其在保护细胞免受 Myc 介导的细胞凋亡中的潜在作用尚未得到研究。我们的结果表明，在表达 v-Myc 的人 U-937 单核细胞和含有条件活性 Myc/雌激素受体 (MycER) 融合蛋白的 Rat1 细胞中，激活的 Myc 增强了癌症药物依托泊苷 (ETO) 和喜树碱 (CAMP) 诱导的细胞凋亡。然而，在两个系统中进行药物处理后，热休克和异位 Hsp70 表达都可以保护细胞免受 Myc 介导的凋亡。 siRNA 介导的 U-937 细胞中 Hsp70 表达的敲低增强了激活的 Myc 对抗肿瘤药物的敏感性增加。针对 Myc 和 Hsp70 分别促进和抑制药物诱导的细胞凋亡的机制，我们发现 v-Myc 刺激细胞色素 c 释放和效应器 caspase-9、-3 和 -7 的激活，但不刺激起始器 caspase-8。抑制 caspase-9 可特异性减少 v-Myc 刺激的细胞凋亡，而抑制 caspase-8 和 -3/7 可减少表达 v-myc 和亲代 ETO 处理的 U-937 细胞的细胞凋亡。有趣的是，Myc 刺激的效应 caspase 激活被抑制，但细胞色素 c 释放不受 Hsp70 表达的影响，这表明 Hsp70 在 caspase-9 和下游 caspase 水平干扰线粒体 Myc 下游的促凋亡功能。总之，Hsp70 似乎在抑制 Myc 介导的细胞凋亡中具有关键功能，因此可能在 Myc 驱动的肿瘤发生中发挥重要作用。 (c) 2007 年 Wiley-Liss, Inc.
The Myc oncoprotein serves a dual function by stimulating cells both towards growth and apoptosis. The latter functions are often abrogated during tumor development. The Hsp70 stress protein is a potent anti-apoptotic molecule, but its potential role in protecting cells from Myc-mediated apoptosis has not been investigated. Our results show that activated Myc potentiated apoptosis induced by the cancer drugs etoposide (ETO) and camptothecin (CAMP) in v-Myc-expressing human U-937 monoblastic cells and in Rat1 cells containing a conditionally active Myc/estrogen receptor (MycER) fusion protein. However, both heat shock and ectopic Hsp70 expression protected the cells from Myc-mediated apoptosis after drug treatment in both systems. The increased susceptibility to the anti-tumor drugs by activated Myc was enhanced by siRNA-mediated knockdown of Hsp70 expression in U-937 cells. Addressing the mechanisms by which Myc and Hsp70 promotes and inhibits drug-induced apoptosis, respectively, we found that v-Myc stimulated cytochrome c release and activation of effector caspase-9, -3 and -7, but not of initiator caspase-8. Inhibition of caspase-9 specifically reduced v-Myc-stimulated apoptosis, whereas inhibition of caspase-8 and -3/7 reduced apoptosis both in v-myc-expressing and parental ETO-treated U-937 cells. Interestingly, Myc-stimulated activation of effector caspases was inhibited, but cytochrome c release was not affected by Hsp70 expression, suggesting that Hsp70 interferes with the proapoptotic function of Myc downstream of mitochondria, at the level of caspase-9 and downstream caspases. In conclusion, Hsp70 seems to have key function in inhibition of apoptosis mediated by Myc and may therefore play an important role in Myc-driven oncogenesis. (c) 2007 Wiley-Liss, Inc.