RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma.

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.

Lu Z ，Shi X ，Gong F ，Li S ，Wang Y ，Ren Y ，Zhang M ，Yu B ，Li Y ，Zhao W ，Zhang J ，Hou G ... -  《-》

Down-regulation of Rictor enhances cell sensitivity to PI3K inhibitor LY294002 by blocking mTORC2-medicated phosphorylation of Akt/PRAS40 in esophageal squamous cell carcinoma.

PI3K/Akt/mTOR signaling pathway plays a vital role in regulating cell survival, differentiation, metabolism and migration, which is frequently hyperactive in a number of cancers, including esophageal squamous cell carcinoma (ESCC). As the core subunit of mTORC2, Rictor is shown to be amplified in ESCC patients' tissues and plays an important role in regulation of Akt. The objective of this study is to evaluate the effects of Rictor knockdown on cell sensitivity to PI3K inhibitor LY294002 in ESCC cells and ESCC xenografts as well as its mechanisms. We found LY294002 obviously restrained cell proliferation in dose-dependent and time-dependent manners by inhibiting PI3K/Akt/mTOR/p70S6K signaling pathway, whereas triggered mTORC2-medicated phosphorylation of Akt (Ser473)/PRAS40 (Thr246) in ECa109 and EC9706 cells. Stable knockdown of Rictor by shRNA enhanced the inhibitory effects of LY294002 on cell proliferative, migration and colony formation, as well as promoted its effects on cell cycle arrest and cell apoptosis in vitro. Furthermore, stable knockdown of Rictor enhanced the antitumor effects of LY294002 by inhibiting tumor growth and promoting cell apoptosis in vivo. Mechanistic assay revealed that knockdown of Rictor could attenuate LY294002-induced phosphorylation of Akt (Ser473)/PRAS40 (Thr246). Our results provide rationale that combined inhibition of Rictor/mTORC2 and PI3K for the treatment of ESCC.

Hou G ，Zhao Q ，Zhang M ，Fan T ，Liu M ，Shi X ，Ren Y ，Wang Y ，Zhou J ，Lu Z ... -  《-》

A dual mTORC1 and mTORC2 inhibitor shows antitumor activity in esophageal squamous cell carcinoma cells and sensitizes them to cisplatin.

Huang Y ，Xi Q ，Chen Y ，Wang J ，Peng P ，Xia S ，Yu S ... -  《-》

Co-targeting PLK1 and mTOR induces synergistic inhibitory effects against esophageal squamous cell carcinoma.

Liu TT ，Yang KX ，Yu J ，Cao YY ，Ren JS ，Hao JJ ，Pan BQ ，Ma S ，Yang LY ，Cai Y ，Wang MR ，Zhang Y ... -  《-》

mTOR inhibitor PP242 increases antitumor activity of sulforaphane by blocking Akt/mTOR pathway in esophageal squamous cell carcinoma.

Sulforaphane (SFN) is a kind of isothiocyanate from cruciferous vegetables with extensive anti-tumor activity. Esophageal squamous cell carcinoma (ESCC) is a popular malignancy in East Asia, East and South Africa, while the more efficient medicines and therapeutic strategies are still lack. This study aims to explore the anti-tumor activity of SFN alone and combined with Akt/mTOR pathway inhibitors as well as the potential molecular mechanism in ESCC. Cell proliferation, migration, cell cycle phase, apoptosis and protein expression were detected with MTT assay, clone formation experiment, wound healing assays, flow cytometry and Western blot, respectively, after ESCC cells ECa109 and EC9706 treated with SFN alone or combined with Akt/mTOR inhibitors. Xenograft models were used to evaluate the efficiency and mechanism of SFN combined with PP242 in vivo. The results showed that SFN significantly inhibited the viability and induced apoptosis of ECa109 and EC9706 cells by increasing expression of Cleaved-caspase 9. SFN combined with PP242, but not MK2206 and RAD001, synergetic inhibited proliferation of ESCC cells. Moreover, compared to SFN alone, combination of SFN and PP242 had stronger inhibiting efficiency on clone formation, cell migratory, cell cycle phase and growth of xenografts, as well as the more powerful apoptosis-inducing effects on ESCC. The mechanism was that PP242 abrogated the promoting effects of SFN on p-p70S6K (Thr389) and p-Akt (Ser473) in ESCC. Our findings demonstrate that PP242 enhances the anti-tumor activity of SFN by blocking SFN-induced activation of Akt/mTOR pathway in ESCC, which provides a rationale for treating ESCC using SFN combined with Akt/mTOR pathway inhibitors.

Lu Z ，Zhang Y ，Xu Y ，Wei H ，Zhao W ，Wang P ，Li Y ，Hou G ... -  《-》