FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway.
FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway.
复制标题
DOI：
10.1158/0008-5472.can-13-1729
复制
发表时间：
2014-03-15
期刊：
影响因子：
11.2
通讯作者：
Gan B
中科院分区：
文献类型：
--
作者：
Lin A;Piao HL;Zhuang L;Sarbassov dos D;Ma L;Gan B
PI 3 K-AKT通路在许多人类癌症中过度活化，目前正在各种临床前和临床试验中测试抑制该通路的几种药物，包括PI 3 K/mTOR双重抑制剂NVP-BEZ 235。已经表明，PI 3 K-AKT途径的药理学抑制导致其他致癌信号传导途径的反馈激活，这可能会限制这些抑制剂在癌症治疗中的临床应用。然而，这种反馈调节的潜在机制仍然不完全清楚。PI 3 K-AKT通路是肾细胞癌（RCC）中经验证的治疗靶点。在这里，我们表明FoxO转录因子在肾癌细胞中响应NVP-BEZ 235处理而促进Ser 473处的AKT磷酸化。FoxO的失活减弱了NVP-BEZ 235诱导的AKT Ser 473磷酸化，并使肾癌细胞对NVP-BEZ 235介导的体外细胞生长抑制和体内肿瘤缩小更敏感。从机制上讲，我们表明FoxOs上调Rictor的表达，Rictor是哺乳动物雷帕霉素靶蛋白复合物2（mTORC 2）的重要组成部分，以响应NVP-BEZ 235处理，并揭示Rictor是NVP-BEZ 235介导的反馈调节中FoxOs的关键下游靶点。最后，我们表明FoxOs通过其他PI 3 K或AKT抑制剂治疗类似地调节对AKT Ser 473磷酸化和肾肿瘤生长的反馈反应。总之，我们的研究揭示了PI 3 K-AKT抑制介导的反馈调节的新机制，并可能将FoxO鉴定为用于对RCC患者进行PI 3 K或AKT抑制剂治疗的新生物标志物，或在RCC治疗中与PI 3 K-AKT抑制协同作用的新治疗靶点。
The PI3K-AKT pathway is hyperactivated in many human cancers, and several drugs to inhibit this pathway, including the PI3K/mTOR dual inhibitor NVP-BEZ235, are currently being tested in various pre-clinical and clinical trials. It has been shown that pharmacological inhibition of the PI3K-AKT pathway results in feedback activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors in cancer treatment. However, the underlying mechanisms of such feedback regulation remain incompletely understood. The PI3K-AKT pathway is a validated therapeutic target in renal cell carcinoma (RCC). Here we show that FoxO transcription factors serve to promote AKT phosphorylation at Ser473 in response to NVP-BEZ235 treatment in renal cancer cells. Inactivation of FoxO attenuated NVP-BEZ235-induced AKT Ser473 phosphorylation, and rendered renal cancer cells more susceptible to NVP-BEZ235-mediated cell growth suppression in vitro and tumor shrinkage in vivo. Mechanistically, we showed that FoxOs upregulated the expression of Rictor, an essential component of mammalian target of rapamycin complex 2 (mTORC2), in response to NVP-BEZ235 treatment, and revealed that Rictor is a key downstream target of FoxOs in NVP-BEZ235-mediated feedback regulation. Finally, we show that FoxOs similarly modulate the feedback response on AKT Ser473 phosphorylation and renal tumor growth by other PI3K or AKT inhibitor treatment. Together, our study reveals a novel mechanism of PI3K-AKT inhibition-mediated feedback regulation, and may identify FoxO as a novel biomarker to stratify RCC patients for PI3K or AKT inhibitor treatment, or a novel therapeutic target to synergize with PI3K-AKT inhibition in RCC treatment.