Functional Validation of H2 Relaxin and Its Downstream Effectors as Mediators, Therapeutic Targets, and Potential Biomarkers of Prostate Cancer Progression
Annual rept. 1 Jun 2008-31 May 2009
CALIFORNIA UNIV DAVIS
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Currently, castrate resistant prostate cancer CRPC remains incurable. The identification of novel pathways that promote castrate resistant growth of prostate cancer CaP cells is critical for the development of successful new therapies to treat CaP. Our group has identified H2 relaxin as a facilitator of CRPC. In the past year, we have generated data that supports a simultaneous inhibition of PKA and B-catenin pathways activated by H2 relaxin causes increased inhibition of both castrate resistant growth and AR signaling, H2 relaxin promotes neuroendocrine differentiation through activation of PKA, steroid hormones cause transactivation of the H2 relaxin promoter, H2 relaxin causes decreased expression of IkappaB-alpha, increased expression of Bcl-2 and increased translocation of NFkappaB to the nucleus, LNCaP stably transfected with H2 relaxin are more resistant to treatment with chemotherapeutic agents, and that inhibition of IKK decreases H2 relaxin mediated chemo-resistance to perifosine. This data implies that H2 relaxin-mediated activation of the PKA and NFkappaB signaling pathways promotes CR growth and chemo-resistance respectively.
- Anatomy and Physiology
- Medicine and Medical Research