Jagged-1 Signaling Pathway in Prostate Cancer Cell Growth and Angiogenesis

摘要

Prostate cancer is the most commonly diagnosed cancer and is the second leading cause of cancer death in the US. Most patients diagnosed with prostate cancer are treatable, but the patients usually die from hormone refractory (HRPC) and metastatic disease. We have previously shown that expression of Notch receptors and their ligands is upregulated in many cancers including prostate cancer. We hypothesize that inactivation of Jagged-1 signaling, which could be directly due to transcriptional inactivation of Jagged-1 or indirectly due to inactivation of Akt/NF-kB, will not only be a novel approach for the treatment of HRPC and metastases but will also sensitize prostate cancer cells to Taxotere-induced killing. We found that down- regulation of Notch-1 and Jagged-1 induced cell growth inhibition and cell apoptosis. We also found that down-regulation of Notch-1 and Jagged-1 decreased the expression and activities of VEGF, MMP-9, uPA. Moreover, down-regulation of Notch-1 and Jagged-1 inhibited the NF-kB DNA binding activity. Consistent with these results, we also found that the down-regulation of Notch-1 and Jagged-1 by genistein enhanced the antitumor activity of taxotere through Notch/Jagged pathway. Collectively, our results suggest that down-regulation of Jagged-1 and Notch-1 could be useful strategy for treatment of prostate cancer. Based on above hypothesis, this proposal seems highly relevant to the mission of the Department of Defense.