Abstract 1408: The insulin-like growth factor receptor I and Pyk2 kinase are up-regulated in urothelial carcinomas and promote motility and invasion of urothelial carcinoma-derived cells

Abstract

Abstract 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. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial-carcinoma-derived cells. Significantly, IGF-IR activation did not affected cell proliferation, suggesting that the IGF-IR may play a more prominent role in promoting the transition to the invasive phenotype in bladder cancer. In this study we demonstrated by immunohistochemical analysis that the IGF-IR expression increased with grade in bladder cancer tissues compared to non-malignant controls. Increased IGF-IR expression in non-tumorigenic T24 urothelial carcinoma cells promoted anchorage independent growth, while targeting of endogenous IGF-IR by shRNA approaches in metastatic T24T cells inhibited colony formation in soft-agar. We also discovered that the focal adhesion protein Pyk2 kinase is activated by IGF-I in urothelial carcinoma-derived cells. Using siRNA approaches, we demonstrated that Pyk2 is critical for IGF-IR-dependent motility and invasion of urothelial cancer cells. In addition, Pyk 2 is critical for IGF-I-dependent activation of the Akt and MAPK pathways, which are critical in the regulation of motility and invasion. Using immunofluorescence and AQUA (Automated Quantitative Analysis) analysis we also discovered that Pyk2 is overexpressed in bladder cancer tissues compared to normal tissue controls. In urothelial carcinoma-derived tissues there is also increased Pyk2 localization in the nucleus compared to normal tissue controls. Our results provide the first evidence for a role of the IGF-IR and Pyk2 in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR and Pyk2 may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR and Pyk2 could represent novel molecular targets in bladder cancer and could also serve as a novel tumor biomarkers 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.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1408. doi:10.1158/1538-7445.AM2011-1408