Novel aspects of vitamin D signalling in prostate cells

Abstract

In addition to the more traditional roles associated with Vitamin D, such as the formation and maintenance of healthy bones, regulation of calcium-phosphate homeostasis and parathyroid hormone regulation, Vitamin D is involved in many other processes in the body including regulation of immune function, neurological function and control of cellular proliferation. Many studies have shown the chemoprotective and therapeutic effects of Vitamin D in the treatment of many ailments including cancer, with many studies investigating as a potential treatment option. Vitamin D therapy has limited success in prostate cancer with tumours becoming resistant to treatment and developing a more aggressive phenotype. Intracrine signalling has been put forward as a theory as to how tumours continue to grow in patients who have undergone androgen ablation therapy; this hypothesis suggests that androgens are synthesized de novo within the tumour microenvironment from adrenal precursors. Cytochrome P450 enzymes are involved in the metabolism of endogenous and exogenous compounds, including steroid hormines, to prevent toxic accumulation. Previous studies in this laboratory have shown that the major hepatic CYP, CYP3A4, can be regulated by the Vitamin D Receptor (VDR) in epithelial cells of the colon when it is liganded to toxic bile acids which in turn facilitates their excretion. This thesis demonstrates a novel finding whereby the VDR directly modulates expression of CYP3A4 in the well known prostate cancer cell line LNCaP. CYP3A4 expression is found to be up-regulated in the presence of the most biologically active form of the vitamin (1,25D) in a LNCaP cells, with a subsequent increase in enzymatic activity and metabolism of testosterone as evidenced by HPLC MS/MS analysis. Interestingly mutation analysis uncovered the finding that the more novel vitamin D response element, ER-6, has important roles to play in the VDR mediated transcriptional response. Additionally VDR was also found to interact with the receptor interacting protein of 140kDa (RIP140) in a ligand dependent manner resulting in dose dependent repression of VDR transcriptional activation while gene silencing of RIP140 resulted in a significant increase in CYP3A4 expression. Considering these results together, CYP3A4 and RIP140 may provide new therapeutic targets in the treatment of prostate cancer.

Date of Award	Jun 2012
Original language	English
Sponsors	Department for Employment and Learning, Northern Ireland
Supervisor	Paul Thompson (Supervisor), Robin Freeburn (Supervisor) & Stephen McClean (Supervisor)