Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 106, Issue -, Pages 1348-1356Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2018.07.075
Keywords
Rictor; LY294002; PI3K; Akt; Esophageal squamous cell carcinoma
Funding
- Open Foundation Project of Pharmacy in Zhejiang Province, China [YKFJ2-010]
- National Natural Science Foundation of Henan Province, China [182300410312]
- Key Scientific Research Project of Universities in Henan Province [17B350003]
- Foundation and Cutting-edge Technology Projects of Henan Province [152300410052]
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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.
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