VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer
AuthorsGoel, Hira Lal
Pursell, Bryan M.
Xi, Hualin Simon
Coleman, Ilsa M.
Nelson, Peter S.
Vessella, Robert L.
Davis, Roger J.
Plymate, Stephen R.
Mercurio, Arthur M.
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AbstractWe 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.
Cancer Discov. 2012 Oct;2(10):906-921. Epub 2012 Jul 9. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/26293
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