Regucalcin is an androgen-target gene in the rat prostate modulating cell-cycle and apoptotic pathways

BACKGROUND Regucalcin (RGN) is a calcium (Ca2+)‐binding protein underexpressed in prostate adenocarcinoma comparatively to non‐neoplastic prostate or benign prostate hyperplasia cases. Moreover, RGN expression is negatively associated with the cellular differentiation of prostate adenocarcinoma, suggesting that loss of RGN may be associated with tumor onset and progression. However, the RGN actions over the control of prostate cell growth have not been investigated. METHODS Androgens are implicated in the promotion of prostate cell proliferation, thus we studied the in vivo effect of androgens on RGN expression in rat prostate. The role of RGN modulating cell proliferation and apoptotic pathways in rat prostate was investigated using transgenic animals (Tg‐RGN) overexpressing the protein. RESULTS In vivo stimulation with 5α‐dihydrotestosterone (DHT) down‐regulated RGN expression in rat prostate. Cell proliferation index and prostate weight were reduced in Tg‐RGN, which was concomitant with altered expression of cell‐cycle regulators. Tg‐RGN presented diminished expression of the oncogene H‐ras and increased expression of cell‐cycle inhibitor p21. Levels of anti‐apoptotic Bcl‐2, as well as the Bcl‐2/Bax protein ratio were increased in prostates overexpressing RGN. Both caspase‐3 expression and enzyme activity were decreased in the prostates of Tg‐RGN. CONCLUSIONS Overexpression of RGN resulted in inhibition of cell proliferation and apoptotic pathways, which demonstrated its role maintaining prostate growth balance. Thus, deregulation of RGN expression may be an important event favoring the development of prostate cancer. Moreover, the DHT effect down‐regulating RGN expression in rat prostate highlighted for the importance of this protein in prostatic physiology. Prostate 74:1189–1198, 2014. © 2014 Wiley Periodicals, Inc.