Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance
Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance
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自噬的诱导抵消了顺铂在获得性耐药的人食管癌细胞中的抗癌作用
DOI：
10.1016/j.canlet.2014.09.020
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发表时间：
2014-12-01
期刊：
影响因子：
9.7
通讯作者：
Liu, Shuwen
中科院分区：
文献类型：
--
作者：
Yu, Le;Gu, Chunping;Liu, Shuwen
以顺铂为基础的化疗常导致获得性耐药。这种抵抗的基础机制仍然不清楚，特别是与自噬反应有关。因此，本研究探讨了自噬在获得性顺铂耐药的人食管癌细胞中顺铂抗癌活性中的作用。顺铂处理后，EC 109细胞出现明显的凋亡和衰老，而顺铂耐药的EC 109/CDDP细胞表现出耐药性。在这方面，顺铂增加ERIC磷酸化，其被MEK抑制剂抑制显著减弱顺铂的细胞毒性和细胞抑制作用。值得注意的是，顺铂优先诱导EC 109/CDDP细胞中的自噬，而不是在EC 109细胞中。此外，自噬的诱导伴随着mTORC 1活性的抑制。通过药理学抑制剂消除自噬或敲低ATG 5/7使EC 109/CDDP细胞再致敏。自噬抑制剂氯喹和顺铂的共同管理显着抑制肿瘤的生长，而顺铂单一疗法未能引起EC 109/CDDP细胞异种移植的裸鼠的抗癌活性。总之，我们的数据暗示自噬反应是顺铂获得性耐药的关键机制，表明自噬是提高顺铂对具有获得性耐药的人食管癌的治疗效率的新靶点。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Cisplatin-based chemotherapy frequently resulted in acquired resistance. The underpinning mechanism of such resistance remains obscure especially in relation to autophagic response. This study thus investigated the role of autophagy in the anticancer activity of cisplatin in human esophageal cancer cells with acquired cisplatin resistance. In response to cisplatin treatment, EC109 cells exhibited substantial apoptosis and senescence whereas cisplatin-resistant EC109/CDDP cells exhibited resistance. In this respect, cisplatin increased ERIC phosphorylation whose inhibition by MEK inhibitor significantly attenuated the cytotoxic and cytostatic effect of cisplatin. Notably, cisplatin preferentially induces autophagy in EC109/CDDP cells but not in EC109 cells. Moreover, the induction of autophagy was accompanied by the suppression of mTORC1 activity. Abolition of autophagy by pharmacological inhibitors or knockdown of ATG5/7 re-sensitized EC109/CDDP cells. Co-administration of an autophagy inhibitor chloroquine and cisplatin significantly suppressed tumor growth whereas cisplatin monotherapy failed to elicit anticancer activity in nude mice xenografted with EC109/CDDP cells. To conclude, our data implicate autophagic response as a key mechanism of acquired resistance to cisplatin, suggesting that autophagy is a novel target to improve therapy efficiency of cisplatin toward human esophageal cancers with acquired resistance. (C) 2014 Elsevier Ireland Ltd. All rights reserved.