Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion.

Autor:	Gupta S; Department of Pathology, University of California San Diego, La Jolla, California., Hau AM; Department of Pathology, University of California San Diego, La Jolla, California., Al-Ahmadie HA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Harwalkar J; Department of Pathology, Cleveland Clinic, Cleveland, Ohio., Shoskes AC; Department of Pathology, Cleveland Clinic, Cleveland, Ohio., Elson P; Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio., Beach JR; Department of Cellular and Molecular Biology, Cleveland Clinic, Cleveland, Ohio., Hussey GS; Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina., Schiemann WP; Department of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio., Egelhoff TT; Department of Cellular and Molecular Biology, Cleveland Clinic, Cleveland, Ohio., Howe PH; Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina., Hansel DE; Department of Pathology, University of California San Diego, La Jolla, California. Electronic address: dhansel@ucsd.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2016 May; Vol. 186 (5), pp. 1351-60. Date of Electronic Publication: 2016 Mar 14.
DOI:	10.1016/j.ajpath.2016.01.008
Abstrakt:	Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-β, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-β signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-β isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E-cadherin. Application of TGF-β induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2- and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-β receptor I using SB431542 ablated TGF-β-induced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-β can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. (Copyright © 2016. Published by Elsevier Inc.)
Databáze:	MEDLINE
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