The role of the cholesterol/27-hydroxycholesterol axis in prostate cancer pathogenesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-388
Mahmoud Ahmad Alfaqih*1 and Donald Patrick McDonnell*2
1Duke University Medical Center, Durham, NC, 2Duke Univ Med Ctr, Chapel Hill, NC
Several studies demonstrated a link between elevated prostatic levels of cholesterol and malignancy indicating that processes regulating cellular cholesterol homeostasis are lost upon transformation. Cellular cholesterol levels reflect a balance between three processes: (1) uptake of low density lipoprotein (LDL) through its membrane receptor (LDLR), (2) efflux of cholesterol through ABCA1 or ABCG1 reverse transporters, and (3) hydroxymethylglutaryl-CoA reductase dependent de novo synthesis. Our preliminary studies on the role of 27-hydroxycholesterol (27HC), a direct metabolite of cholesterol, in prostate cancer pathogenesis shows that treatment of LNCaP cells with 27HC results in a reduction in the expression of LDLR, accompanied by a concurrent induction of ABCG1, implicating a potential role of 27HC in regulating the above processes and thus cholesterol flux in the prostate. Intriguingly, the above gene expression changes tracked with inhibition of LNCaP cell proliferation.  In prostatic tissues, 27HC is synthesized by the cytochrome p450 enzyme, CYP27A1. Given the fact that CYP27A1 levels are down-regulated in advanced disease when compared to normal prostatic epithelial cells or early stage tumors, we believe that CYP27A1-mediated conversion of cholesterol into 27HC maintains normal cholesterol levels and that down-regulation of this enzyme contributes to tumor phenotype.  Studies are underway to underline the contribution of the cholesterol/27HC axis to tumor pathology.

Disclosure: DPM: Principal Investigator, Novartis Pharmaceuticals, Principal Investigator, Pfizer, Inc., Principal Investigator, GlaxoSmithKline, Research Funding, Lilly USA, LLC. Nothing to Disclose: MAA

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