1. VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer.
- Author
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Goel HL, Chang C, Pursell B, Leav I, Lyle S, Xi HS, Hsieh CC, Adisetiyo H, Roy-Burman P, Coleman IM, Nelson PS, Vessella RL, Davis RJ, Plymate SR, and Mercurio AM
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Humans, JNK Mitogen-Activated Protein Kinases genetics, JNK Mitogen-Activated Protein Kinases metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, Polycomb Repressive Complex 1 genetics, Prostatic Neoplasms genetics, RNA Interference, RNA, Small Interfering, Receptor, IGF Type 1 genetics, Signal Transduction genetics, Transcription, Genetic, Transcriptional Activation, Transplantation, Heterologous, Vascular Endothelial Growth Factor A genetics, Neuropilin-2 metabolism, Polycomb Repressive Complex 1 metabolism, Prostatic Neoplasms metabolism, Receptor, IGF Type 1 metabolism, Vascular Endothelial Growth Factor A metabolism
- 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.
- Published
- 2012
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