Protein Phosphatase 2A Signaling in Human Prostate Cancer
Annual rept. 1 Feb 2012-6 May 2013
UNIVERSITY OF SOUTH ALABAMA MOBILE
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Advanced prostate cancers PCa treated with first line androgen-deprivation therapy ADT eventually relapse in a hormone refractory or castration-resistant CR form. Relapsed disease is highly aggressive and poses an increased risk of morbidity and death. Previously, we demonstrated that PPP2CA, which encodes the catalytic-subunit alpha-isoform of the protein phosphatase 2A PP2AC , is downregulated in CR PCa. The level of PP2AC was decreased in majority of CR PCa cell lines and cancer lesions as compared to the adjacent normalbenign tumor tissues. Under this project, we have utilized multiple approaches to demonstrate a functional role of PP2A in human prostate cancer progression. We have shown that PP2A downregulation promotes growth, androgen depletion-resistance and aggressive behavior of prostate cancer cells. We have also developed in vivo experimental support for a suppressor role of PP2A in prostate cancer progression using orthotopic mouse model. Furthermore, we delineated the molecular mechanisms involved in the PP2A-mediated growth and aggressive phenotypes of PCa cells. We observed PP2A downregulation facilitates castration-resistant growth of PCa cells in both androgen receptor AR- dependent and independent manners in AR expressing LNCaP and C4-2 cells. Moreover, we identified that PPP2CA downregulation favors EMT, migration and invasion of PCa cells through Akt-dependent activation of -catenin and NF- B pathway. Our data strongly suggest that downregulation of PP2A is associated with human prostate cancer progression and restoration of PP2A activity may be an effective approach for the treatment of the advanced disease.
- Medicine and Medical Research