Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Vitamin D receptor activity is differentially affected by the co-regulator Hic-5 in prostate and stromal cells

Solomon, Joshua (2013) Vitamin D receptor activity is differentially affected by the co-regulator Hic-5 in prostate and stromal cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (1MB) | Preview


Prostate cancer patients treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-dihydroxyvitamin D3 (1,25D3), is a potential adjuvant therapy that confers anti-proliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D3 therapy in CRPC patients has not been assessed. Transforming growth factor-β (TGF-β), which is associated with the development of tumorigenic “reactive stroma” in prostate cancer, induced VDR expression in the human WPMY-1 prostate stromal cell line. Similarly, TGF-β enhanced 1,25D3-induced upregulation of CYP24A1, which metabolizes of 1,25D3 and thereby limits VDR activity. Ablation of Hic-5, a TGF-β-inducible nuclear receptor co-regulator, inhibited basal VDR expression, 1,25D3-induced CYP24A1 expression and metabolism of 1,25D3 and TGF-β-enhanced CYP24A1 expression. Luciferase reporter mapping of the CYP24A1 promoter identified a Hic-5-responsive sequence 392-451 bp upstream of the transcription start site (TSS). Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D3 at a lower concentration by a pathway independent of CYP24A1. The sensitivity of Hic-5-expressing LNCaP cells to 1,25D3-induced growth inhibition was accentuated in co-culture with Hic-5-ablated WPMY-1 cells. Therefore, my findings suggest that the search for mechanisms to sensitize prostate cancer cells to the anti-proliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment. By acting as a co-regulator with distinct effects on VDR transactivation in prostate cancer and stromal cells, Hic-5 could exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Solomon, Joshuajos62@pitt.eduJOS62
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDeFranco, Donald Bdod1@pitt.eduDOD1
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Committee MemberSingh, Shivendra Vsvs2@pitt.eduSVS2
Committee MemberSchmidt, Martin Cmcs2@pitt.eduMCS2
Committee MemberWalker, William Hwalkerw@pitt.eduWALKERW
Date: 12 September 2013
Date Type: Publication
Defense Date: 5 August 2013
Approval Date: 12 September 2013
Submission Date: 10 September 2013
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 108
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: nuclear receptors, vitamin D, co-regulators, prostate cancer, microenvironment
Additional Information: Updated to include bookmark for title page
Date Deposited: 12 Sep 2013 19:56
Last Modified: 15 Nov 2016 14:15


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item