Functional Validation of H2 Relaxin, and its Downstream Effectors, as Mediators, Therapeutic Targets and Potential Biomarkers of Prostate Cancer Progression
Abstract
The purpose of this study was to investigate the mechanism by which H2 relaxin mediates castrate resistant (CR) prostate cancer (CaP), and to determine whether H2 relaxin can be used as a biomarker to identify CaP progression. Elucidating the mechanisms by which prostate cancer disease progression occurs is critical to the development of new treatments for this disease, while the identification of a biomarker will facilitate the detection of CaP progression. We have demonstrated H2 relaxin (RLN2) facilitates castrate resistant (CR) growth of prostate cancer (CaP) cells through PI3K/Akt/Beta- catenin-mediated activation of the androgen receptor (AR) pathway. As inhibition of this pathway caused only approximately 50% reduction in CR growth, we set out to identify additional RLN2-activated pathways that contribute to CR growth. Inhibition of PKA attenuated RLN2-mediated AR activity, inhibited proliferation and caused a small but significant increase in apoptosis. Combined inhibition of the PKA and NF B signaling pathways via inhibition of PKA and Akt induced significant apoptosis and dramatically reduced clonogenic potential, outperforming docetaxel, the standard of care treatment for CR CaP. Immunohistochemical (IHC) analysis of tissue microarrays (TMA) in combination with multispectral quantitative imaging comparing RLN2 levels in patients with BPH, PIN and CaP determined that RLN2 is significantly upregulated in CaP vs BPH (p=0.002). In summary, our data indicate that simultaneous inhibition of PKA and NF- B would prevent RLN2 mediated cell survival in CaP, and that in a setting of elevated RLN2 expression this combined inhibition is superior to docetaxel. The number of patients who would potentially benefit from this study is likely to be extensive since a significant portion of CaP patients overexpress RLN2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2011
- Accession Number
- ADA554634
Entities
People
- Ralph W. White
Organizations
- University of California