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 cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.
Highlights
Bladder cancer is a major epidemiological problem, whose incidence continues to rise
We showed that IGFIR-dependent cell motility and invasion required the activation of the Akt and MAPK pathway [17,18] and Akt- and ERKdependent activation of paxillin, which upon IGF-I-stimulation colocalized with focal adhesion kinase (FAK) in dynamic adhesions at the leading edge of migrating urothelial cancer cells and was critical for IGF-I-induced motility of these cells [17]
We show that while focal adhesion kinases (FAK) was not required for IGF-IRdependent signaling and motility of invasive urothelial carcinoma cells, the FAK-related Proline-rich tyrosine kinase 2 (Pyk2) [19,20] was strongly activated by IGFI in urothelial carcinoma cells, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways
Summary
Bladder cancer is a major epidemiological problem, whose incidence continues to rise. The majority of bladder tumors (,70%) are low-grade noninvasive papillary tumors that do not penetrate the epithelial basement membrane (Ta stage). The remainder comprise tumors that have penetrated the basement membrane but not invaded the muscle layer of the bladder wall (T1 stage) and muscle-invasive tumors (T2, T3 and T4 stages) [2,3,4]. The prognosis for low-grade tumors is generally good, but about 10%–15% of these patients will later develop invasive disease. For invasive tumors the prognosis is much less favorable, with only 50% survival at 5 years. Invasive tumors frequently progress to life-threatening metastases, which is associated with a 5 year survival rate of 6% [3,4]. Understanding the mechanisms that regulate bladder tumor invasion is critical to predict and treat this devastating condition in bladder cancer patients
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