Activation of insulin-like growth factor signaling induces apoptotic cell death under prolonged hypoxia by enhancing endoplasmic reticulum stress response
Activation of insulin-like growth factor signaling induces apoptotic cell death under prolonged hypoxia by enhancing endoplasmic reticulum stress response
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DOI：
10.1158/0008-5472.can-06-3389
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Inoue, Masahiro
中科院分区：
文献类型：
--
作者：
Endo, Hiroko;Murata, Kohei;Inoue, Masahiro
实体瘤中的恶性细胞在长时间缺氧下存活，并且可以成为对当前癌症疗法的抗性的来源。哺乳动物雷帕霉素靶蛋白（mTOR）是胰岛素样生长因子（IGF）通路的下游分子之一，是整合多种环境和营养线索的翻译关键调节因子。已知mTOR的活性在癌细胞中的缺氧条件下被抑制，而这种抑制对细胞存活的贡献尚未阐明。我们发现，刺激IGF信号引发caspase依赖性凋亡的低，氧张力下的两个癌细胞系，科洛320和AsPC-1。与BAD磷酸化水平的增加同时，细胞死亡并不伴随着细胞色素c从线粒体释放。当磷脂酰肌醇3-激酶（PI 3 K）或mTOR活性被抑制时，细胞被从凋亡中拯救出来，这表明这些信号在观察到的细胞死亡中至关重要。IGFs和胰岛素增强内质网（ER）应激反应，通过在缺氧条件下诱导CCAAT/增强子结合蛋白同源蛋白（CHOP）蛋白和X盒蛋白-1剪接来监测，这种反应通过抑制PI 3 K和mTOR活性来抑制。IGF-诱导的细胞死亡在缺氧条件下被阻止与放线菌酮治疗，这表明从头蛋白质合成是必需的。事实上，用小发夹RNA抑制CHOP蛋白水平减少了细胞死亡。总之，这些数据表明，在缺氧条件下刺激IGF信号通过增强ER应激反应引起细胞凋亡。
Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Mammalian target of rapamycin (mTOR), one of the downstream molecules of the insulin-like growth factor (IGF) pathway, is a key regulator of translation, integrating multiple environmental and nutritional cues. The activity of mTOR is known to be suppressed under hypoxic conditions in cancer cells, whereas the contribution of this suppression to cell survival has not yet been clarified. We show that stimulating IGF signaling provoked caspase-dependent apoptosis under low, oxygen tension in two cancer cell lines, COLO 320 and AsPC-1. In concurrence with increased levels of BAD phosphorylation, cell death was not accompanied by cytochrome c release from mitochondria. The cells were rescued from apoptosis when phosphatidylinositol 3-kinase (PI3K) or mTOR activity was inhibited, suggesting that these signals are critical in the observed cell death. IGFs and insulin enhanced the endoplasmic reticulum (ER) stress response as monitored by induction of the CCAAT/enhancer binding protein homologous protein (CHOP) proteins and the X box protein-1 splicing under hypoxic conditions, and this response was suppressed by inhibiting PI3K and mTOR activity. IGF-induced cell death under hypoxic conditions was prevented by treatment with cycloheximide, suggesting that de novo protein synthesis is required. Indeed, suppression of CHOP protein levels with small hairpin RNA reduced cell death. Taken together, the data suggest that stimulating IGF signaling under hypoxic conditions provokes apoptosis by enhancing the ER stress response.