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Biomed Pharmacother. 2018 Oct;106:1348-1356. doi: 10.1016/j.biopha.2018.07.075. Epub 2018 Jul 23.

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

Author information

1
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
2
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
3
Department of Oncology, People's Hospital of Henan Province, Zhengzhou 450003, China.
4
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of Cancer Chemoprevention, Henan Province, Zhengzhou 450001, China. Electronic address: lzm310@zzu.edu.cn.

Abstract

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.

KEYWORDS:

Akt; Esophageal squamous cell carcinoma; LY294002; PI3K; Rictor

PMID:
30119206
DOI:
10.1016/j.biopha.2018.07.075
[Indexed for MEDLINE]

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