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
Biochemistry | Cancer Biology | Cell Biology | Molecular Biology | Neoplasms
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.
DOI of Published Version
Cancer Discov. 2012 Oct;2(10):906-921. Epub 2012 Jul 9. Link to article on publisher's site
Goel HL, Chang C, Pursell BM, Leav I, Lyle S, Xi HS, Hsieh C, Adisetiyo H, Roy-Burman P, Coleman IM, Nelson PS, Vessella RL, Davis RJ, Plymate SR, Mercurio AM. (2012). VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer. Cancer Biology Publications. https://doi.org/10.1158/2159-8290.CD-12-0085. Retrieved from https://escholarship.umassmed.edu/cancerbiology_pp/209