RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma
RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma
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DOI：
10.1016/j.apsb.2020.01.010
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发表时间：
2020-06-01
影响因子：
14.5
通讯作者：
Hou, Guiqin
中科院分区：
文献类型：
--
作者：
Lu, Zhaoming;Shi, Xiaojing;Hou, Guiqin
mTORC 1/mTORC 2通路在多种肿瘤中存在异常调节，mTORC 1抑制剂已用于多种肿瘤的临床治疗，但mTORC 2在肿瘤发生中的作用机制尚不清楚。本文主要探讨mTORC 2在食管鳞状细胞癌（ESCC）中的潜在作用及其对细胞对mTOR抑制剂敏感性的影响。我们发现，RICTOR，mTORC 2的关键因子，和p-AKT（Ser 473）在ESCC中过度激活，它们的过表达与ESCC患者的淋巴结转移和肿瘤-淋巴结-转移（TNM）期有关。此外，我们发现mTORC 1/mTORC 2抑制剂PP 242比mTORC 1抑制剂RAD 001对ESCC细胞表现出更有效的抗增殖作用，这是由于RAD 001触发AKT信号的反馈激活。另一方面，我们证实下调RICTOR在ECa 109和EC 9706细胞中的表达可抑制细胞的增殖和迁移，并诱导细胞周期阻滞和凋亡。值得注意的是，RICTOR的稳定敲低显著抑制了RAD 001诱导的AKT/PRAS 40信号的反馈激活，并增强了PP 242对AKT和PRAS 40磷酸化的抑制效力，从而增强了RAD 001和PP 242的体内外抗肿瘤作用。我们的研究结果强调，选择性靶向mTORC 2可能是未来治疗ESCC的一种有前途的治疗策略。(C)2020中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.