Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
Cancer Lett. 2013 Aug 19;336(2):319-24. doi: 10.1016/j.canlet.2013.03.021. Epub 2013 Mar 22.
Herein, we show that the constitutive overexpression of Redd1, a negative regulator of mTORC1, induces Akt activation in lung cancer cells. Akt phosphorylation was reduced to basal levels by Rictor siRNA, suggesting the involvement of mTORC2 in this process. Perifosine and PP242, selective inhibitors of Akt and mTORC1/2, respectively, efficiently suppressed the Akt phosphorylation that was induced by the sustained overexpression of Redd1 and increased the sensitivity of the cells to cisplatin. Therefore, the sustained overexpression of Redd1 leads to mTORC1 inhibition and to consequent Akt activation that is involved in cell survival. This finding highlights the importance of Akt activation as a therapeutic target to overcome resistance to chemotherapy.
在此，我们表明 Redd1 的组成性过表达，作为 mTORC1 的负调节剂，会在肺癌细胞中诱导 Akt 的激活。Akt 磷酸化被 Rictor siRNA 降低到基础水平，表明 mTORC2 在此过程中参与。分别作为 Akt 和 mTORC1/2 的选择性抑制剂的 Perifosine 和 PP242，有效地抑制了 Redd1 持续过表达诱导的 Akt 磷酸化，并增加了细胞对顺铂的敏感性。因此，Redd1 的持续过表达导致 mTORC1 抑制和随后 Akt 的激活，这涉及细胞存活。这一发现强调了 Akt 激活作为克服化疗耐药性的治疗靶点的重要性。
