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Down-regulation of Rictor enhances cell sensitivity to PI3K inhibitor LY294002 by blocking mTORC2-medicated phosphorylation of Akt/PRAS40 in esophageal squamous cell carcinoma
- Source :
- Biomedicinepharmacotherapy = Biomedecinepharmacotherapie. 106
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Cell cycle checkpoint
Time Factors
Morpholines
Cell
Down-Regulation
Mice, Nude
Antineoplastic Agents
Apoptosis
Mechanistic Target of Rapamycin Complex 2
mTORC2
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Phosphorylation
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Cell Proliferation
Phosphoinositide-3 Kinase Inhibitors
Pharmacology
Dose-Response Relationship, Drug
Cell growth
Chemistry
digestive, oral, and skin physiology
General Medicine
Xenograft Model Antitumor Assays
Tumor Burden
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Neoplastic
030104 developmental biology
medicine.anatomical_structure
Rapamycin-Insensitive Companion of mTOR Protein
Chromones
030220 oncology & carcinogenesis
Cancer research
Female
Esophageal Squamous Cell Carcinoma
Signal transduction
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 19506007
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Biomedicinepharmacotherapy = Biomedecinepharmacotherapie
- Accession number :
- edsair.doi.dedup.....e681f07e8fe38554f181797a66927186