Abstract 5057: The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and MAPK-dependent activation of paxillin

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. Aberrant IGF-IR signaling is implicated in several types of tumors, including carcinomas of the lung, breast, prostate, pancreas, liver and colon. However, whether the IGF-IR contributes to the transforming phenotype of urothelial cells has not been clearly established but recent data suggest that the IGF-IR is over-expressed in bladder cancer. In this study we demonstrated by immunohistochemical analysis that the IGF-IR is over-expressed in invasive bladder cancer (T3/T4) tissues compared to non-malignant controls. We have also characterized the mechanism of action of the IGF-IR in cancer urothelial cells using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion through extracellular matrix. These effects required the activation of the Akt and MAPK pathways and IGF-I induced Akt- and MAPK-dependent phosphorylation of paxillin, which relocated at dynamic focal adhesions at the protruding edge of migrating urothelial cancer cells. Using siRNA strategies we also demonstrated that paxillin was necessary for promoting IGF-I-mediated motility and invasion in bladder cancer cells. In conclusion, our results provide the first evidence for a role of the IGF-IR in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR could represent a novel molecular target in bladder cancer and could also serve as a novel tumor biomarker for diagnosis and possibly prognosis of bladder tumors. This work has been supported by the Benjamin Perkins Bladder Cancer Fund, the Martin Greitzer Fund and National Institutes of Health Grants RO1 DK068419 (A.M.) and RO1 CA39481 and RO1 CA047282 (R.V.I.). §Present address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5057.