Regulation of Androgen Receptor by Lyn Tyrosine Kinase in Advanced Prostate Cancer

Introduction: It is proposed that advanced Prostate Cancer (PCa) tumors develop mechanisms, which re-activate the androgen receptor (AR) axis via oncogenic pathways, in which tyrosine kinases play a crucial role. Genetic manipulation of several tyrosine kinases in vivo revealed that only a knockout of Lyn tyrosine Kinase, compromised prostate gland development suggesting that Lyn plays a critical role in prostate development. Given that AR plays a central role in normal prostate development and survival of PCa cells. We hypothesize that Lyn facilitates CRPC thus enhancing AR transcriptional activity which ultimately promotes prostate cancer cell survival. Method: Human specimens from untreated and CRPC were submitted to Immunohistochemistry. PCa cells were treated with Lyn siRNA and submitted to Western blot, qRT-PCR, and apoptosis analysis. Lyn WT and dominant negative (DN) as well as siRNA were tested for their ability to modulate AR transcription activity using PSA luciferase reporter promoter. Results: We found that Lyn expression correlates with PCa progression to CRPC in both in vitro and in vivo. Lyn is up-regulated in androgen independent compared to androgen dependent PCa cell lines and is highly expressed in CRPC compared to naive tumors. Targeting Lyn expression or activity abrogates AR transcription activity while its overexpression enhances it. Interestingly, suppressing Lyn expression results in a decrease of AR protein expression and PSA expression thereby enhancing cell apoptosis. Conclusion: Together, these results suggest that Lyn plays a role in CRPC development and that inhibiting Lyn expression could be considered as a potential therapeutic target for CRPC.