title: Mammalian target of rapamycin complex 2 (mTORC2) is a critical determinant of bladder cancer invasion.
abstract: Bladder cancer is the fourth most common cause of cancer in males in the United States. Invasive behavior is a major determinant of prognosis. In this study, we identified mammalian target of rapamycin complex 2 (mTORC2) as a central regulator of bladder cancer cell migration and invasion. mTORC2 activity was assessed by the extent of phosphorylation of Ser473 in AKT and determined to be approximately 5-fold higher in specimens of invasive human bladder cancer as opposed to non-invasive human bladder cancer. The immortalized malignant bladder cell lines, UMUC-3, J82 and T24 demonstrated higher baseline mTORC2 activity relative to the benign bladder papilloma-derived cell line RT4 and the normal urothelial cell line HU1. The malignant bladder cancer cells also demonstrated increased migration in transwell and denudation assays, increased invasion of matrigel, and increased capacity to invade human bladder specimens. Gene silencing of rictor, a critical component of mTORC2, substantially inhibited bladder cancer cell migration and invasion. This was accompanied by a significant decrease in Rac1 activation and paxillin phosphorylation. These studies identify mTORC2 as a major target for neutralizing bladder cancer invasion.
authors: Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors: Sounak
authors: S
authors: Gupta
authors: Andrew M
authors: AM
authors: Hau
authors: Jordan R
authors: JR
authors: Beach
authors: Jyoti
authors: J
authors: Harwalker
authors: Elisabetta
authors: E
authors: Mantuano
authors: Steven L
authors: SL
authors: Gonias
authors: Thomas T
authors: TT
authors: Egelhoff
authors: Donna E
authors: DE
authors: Hansel
mesh_terms: D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein