Title

VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer

UMMS Affiliation

Department of Cancer Biology; Program in Molecular Medicine

Publication Date

10-2012

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Molecular Biology | Neoplasms

Abstract

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

10.1158/2159-8290.CD-12-0085

Source

Cancer Discov. 2012 Oct;2(10):906-921. Epub 2012 Jul 9. Link to article on publisher's site

Journal/Book/Conference Title

Cancer discovery

Related Resources

Link to Article in PubMed

PubMed ID

22777769

Link to Full Text

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