VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer
Department of Cancer Biology; Program in Molecular Medicine
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.
Goel, Hira Lal; Chang, Cheng; Pursell, Bryan M.; Leav, Irwin; Lyle, Stephen; Xi, Hualin Simon; Hsieh, Chung-Cheng; Adisetiyo, Helty; Roy-Burman, Pradip; Coleman, Ilsa M.; Nelson, Peter S.; Vessella, Robert L.; Davis, Roger J.; Plymate, Stephen R.; and Mercurio, Arthur M., "VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer" (2012). Cancer Biology Publications and Presentations. Paper 209.