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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >ATF6α-Rheb-mT0R signaling promotes survival of dormant tumor cells in vivo
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ATF6α-Rheb-mT0R signaling promotes survival of dormant tumor cells in vivo

机译：ATF6α-Rheb-mT0R信号增强体内休眠肿瘤细胞的存活率

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摘要

The pathways that allow quiescent disseminated cancer cells to survive during prolonged dormancy periods are unknown. Here, we identify the transcription factor ATF6α as a pivotal survival factor for quiescent but not proliferative squamous carcinoma cells. ATF6α is essential for the adaptation of dormant cells to chemotherapy, nutritional stress, and, most importantly, the in vivo microenviron-ment. Mechanism analysis showed that MKK6 and p38α/β contribute to regulating nuclear translocation and transcriptional activation of ATF6α in dormant cancer cells. Downstream, ATF6α induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt. Down-regulation of ATF6α or Rheb reverted dormant tumor cell resistance to rapamycin and induced pronounced killing only of dormant cancer cells in vivo. Knocking down ATF6α also prolonged the survival of nude mice bearing dormant tumor cells. Targeting survival signaling by the ATF6α-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods.
机译：允许静态扩散的癌细胞在延长的休眠期中存活的途径尚不清楚。在这里，我们确定转录因子ATF6α为静止但非增殖的鳞状细胞的关键生存因子。 ATF6α对于休眠细胞适应化学疗法，营养应激以及最重要的是体内微环境至关重要。机理分析表明，MKK6和p38α/β有助于调节休眠癌细胞中的核转运和ATF6α的转录激活。在下游，ATF6α通过Rheb的上调和独立于Akt的mTOR信号的激活来诱导存活。 ATF6α或Rheb的下调恢复了休眠的肿瘤细胞对雷帕霉素的抗性，并仅在体内诱导明显杀死了休眠的癌细胞。敲除ATF6α还可以延长带有休眠肿瘤细胞的裸鼠的存活率。通过ATF6α-Rheb-mTOR途径在休眠的肿瘤细胞中靶向生存信号可能有助于消除休眠期间的残留疾病。

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