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.

Highlights

  • Bladder cancer accounts for greater than 70,000 new cancer cases in the United States annually, with an estimated global incidence of 386,000 cases per year [1,2]

  • Results mammalian target of rapamycin complex 2 (mTORC2) signaling is increased in invasive human bladder cancers

  • We evaluated mTORC2 activity in samples of LG Urothelial carcinoma (UCa), HG UCa, and HG UCa with invasion by determining phosphorylation of AKT at Ser473 (p-Ser473)

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Summary

Introduction

Bladder cancer accounts for greater than 70,000 new cancer cases in the United States annually, with an estimated global incidence of 386,000 cases per year [1,2]. Urothelial carcinoma (UCa) represents approximately 95% of all bladder cancers, with patient outcomes primarily influenced by pathological grade and stage [3]. Grade is a primary contributor to behavior in non-invasive UCa, which is subdivided into lowgrade and high-grade categories. Low-grade disease shows frequent local recurrence on the bladder surface, but rare progression to invasive disease [4]. High-grade disease progresses to invasion in 40-50% of patients [5]. Disease-specific survival diminishes with increasing pathological stage (i.e., depth of invasion into the bladder wall), despite therapeutic intervention

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