Date of Award

1-1-2014

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xvi, 246 pages) : illustrations (some color)

Dissertation/Thesis Chair

Martin P.R. Tenniswood

Committee Members

JoEllen Welsh, Douglas S Conklin, Thomas Begley, Michael DiPersio

Keywords

AR, Metabolism, miRNA, Testosterone, VDR, Vitamin D, Prostate, Cholecalciferol, Drug-nutrient interactions, Antineoplastic agents, Antiandrogens

Subject Categories

Molecular Biology

Abstract

Contrary to the common belief that prostate cancer is a hormone dependent disease, the incidence of prostate cancer and associated mortality actually increases significantly after serum androgen levels decline. This led us to hypothesize that androgen depletion in elder men is an underlying cause for the development and progression of prostate cancer. In addition, serum vitamin D3 levels also decline in older men. Epidemiological and experimental data support an anti-neoplastic activity of vitamin D3 in colorectal and breast cancers through regulation of cell proliferation, apoptosis, cell differentiation and metastasis. The effects of vitamin D3 on prostate cancer biology are less well defined and the results are often conflicting. Our studies demonstrate an extensive crosstalk between androgen- and vitamin D3-mediated signaling, which suggests that androgens are modifiers of vitamin D3 activity in prostate cancer cells. Using in vitro model systems to recapitulate the hormonal environment in androgen and vitamin D3 replete prostate cancer patients, we have found that androgen and vitamin D3 coordinately inhibit cell growth and induce cell differentiation via modulation of energy metabolic pathways. Concurrent microarray analyses suggest that androgen and vitamin D3 together modulate mRNA and miRNA levels directly via binding to their cognate receptors and activating/repressing gene expression, and indirectly by modulating the levels of key transcription factors, including c-Myc and PPARα, or through miRNA-mediated mRNA degradation or translational repression. This leads to changes in global gene expression that affects several cellular processes, cell proliferation and lipid metabolism. Moreover, changes in neutral lipid production and deposition are associated with the effect of androgen and vitamin D3 on TCA cycle activity via modulation of zinc transporter levels. These phenotypic changes suggest that androgen and vitamin D3 are key modulators determining the fate of citrate in prostate cancer cells. By preventing citrate utilization for energy production, androgen and vitamin D3 maintain prostate cancer cells in a more differentiated state and prevent cancer progression. This further suggests that vitamin D3 and androgen supplementation, under proper guidance, will be beneficial for disease management.

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