American Association for Cancer Research
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Supplementary Figure 4 from VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer

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journal contribution
posted on 2023-04-03, 20:20 authored by Hira Lal Goel, Cheng Chang, Bryan Pursell, Irwin Leav, Stephen Lyle, Hualin Simon Xi, Chung-Cheng Hsieh, Helty Adisetiyo, Pradip Roy-Burman, Ilsa M. Coleman, Peter S. Nelson, Robert L. Vessella, Roger J. Davis, Stephen R. Plymate, Arthur M. Mercurio

PDF file - 454K, Role of JNK/c-Jun in regulating NRP2 expression in prostate carcinoma cells



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.Significance: These results identify a causal role for NRP2 and VEGF/NRP2 signaling in the behavior of aggressive prostate cancers by a mechanism that involves regulation of Bmi-1, a transcriptional repressor implicated in the etiology of prostate cancer induced by loss of PTEN function, and the repression of the IGF-IR. The therapeutic implications are significant because combined inhibition of NRP2 and IGF-IR overcomes the resistance induced by targeting each receptor individually. Cancer Discov; 2(10); 906–21. ©2012 AACR.This article is highlighted in the In This Issue feature, p. 857.

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