title: Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion.
abstract: 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.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Sounak
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hau
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Harwalkar
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Shoskes
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.affiliation: Department of Cellular and Molecular Biology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Beach
authors.affiliation: Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: George S
authors.initials: GS
authors.lastname: Hussey
authors.affiliation: Department of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.affiliation: Department of Cellular and Molecular Biology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Egelhoff
authors.affiliation: Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Howe
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California. Electronic address: dhansel@ucsd.edu.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hansel
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000473:pathology* / Q000503:physiopathology; D014746:Vimentin / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D015820:Cadherins; D004149:Dioxoles; D046912:Multiprotein Complexes; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases