Abstract 3311: The cholesterol/ 27-hydroxycholesterol axis is a novel therapeutic target in castrate resistant prostate cancer

2014 
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The most recent estimates indicate that men have a seventeen percent chance of developing invasive prostate cancer (PCa) over their lifetime. This makes PCa the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. Although PCa almost always develops resistance to androgen-deprivation therapy, both androgen receptor (AR) itself and the processes downstream of the receptor remain active and are necessary for cancer progression and thus continue to be viable targets for therapeutic intervention. In this regard, it is of significance that several independent studies demonstrate a link between elevated intra-prostatic levels of cholesterol and the presence of malignancy. This puts into context our current finding that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol, regulates pathways and processes that oppose AR action. For example, AR activation results in a net uptake of cholesterol by PCa cells and enhances denovo lipogenesis, while 27HC down-regulates genes involved in cholesterol uptake and activates those involved in its efflux. More importantly, we show that treatment of PCa cell lines with 27HC inhibits their proliferation, an activity that is reversed upon supplementing the cells with an exogenous source of cholesterol or upon over-expression of low density lipoprotein receptor (LDLR), a membrane protein that mediates the uptake of cholesterol. In prostatic tissues, 27HC is synthesized directly from cholesterol by the cytochrome P450 enzyme, CYP27A1. To further highlight the above axis as a novel therapeutic target, using data mining approaches from clinical databases, we show that (1) transcript levels of CYP27A1 are dramatically down-regulated during PCa progression and (2) patients whose tumors express high levels of CYP27A1transcript exhibit longer disease free survival. Most notably, we were able to show that over-expression of CYP27A1 inhibits the proliferation of PCa cell lines in vitro and delays the growth of xenografts in castrated immune-deficient mice. In summary, our data thus far strongly implicates that CYP27A1 is a potential tumor suppressor in PCa and highlights the cholesterol/27HC axis as a target for the development of novel therapeutics for castrate resistant disease. Citation Format: Mahmoud A. Alfaqih, Erik R. Nelson, Rachid Safi, Jeff Jasper, Ching-yi Chang, Stephen J. Freedland, Donald P. McDonnell. The cholesterol/ 27-hydroxycholesterol axis is a novel therapeutic target in castrate resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3311. doi:10.1158/1538-7445.AM2014-3311
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