Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis.

The down-regulation of SR-BI significantly impacts PSA production of prostate cancer cells, as well as the viability of C4-2 cells in the presence and absence of HDL. This may indicate a deficiency in cholesterol availability to the androgen synthesis pathway or may implicate a role for SR-BI in prostate cancer signal transduction pathways.

Advanced prostate cancer (CaP) is often treated with androgen deprivation therapy (ADT). Despite high initial success rates of this therapy, recurrence of the cancer in a castration-resistant (CRPC) form is inevitable. It has been demonstrated that, despite the low levels of circulating androgens resulting from ADT, intratumoral androgen levels remain high and androgen receptor activation persists. Recently, it was discovered that de novo androgen synthesis is occurring within the tumor cells themselves, thus providing a potential mechanism for the high endogenous concentrations. A common upstream precursor in this steroidogenic pathway is cholesterol. For many decades, the breakdown of cholesterol homeostasis in cancer has been the focus of research, but this was largely to elucidate its involvement in maintaining membrane integrity and cell signaling. De novo steroidogenesis has provided a new avenue for cholesterol research and reinforces the importance of understanding the mechanisms that lead to the alterations in cholesterol regulation in the progression to CRPC. The findings to date suggest that cholesterol homeostasis is altered to support de novo androgen synthesis and appear to facilitate disease progression. We further propose that a better understanding of the link between cholesterol and de novo androgen synthesis in CaP progression may provide opportunities for novel therapeutic intervention, namely via eliminating sources of the precursor cholesterol. This review summarizes the implications of cholesterol dysregulation in CaP and particularly in the post-ADT castration-resistant state, as well as the potential implementation of novel therapies targeting these cholesterol sources.

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BACKGROUND: Prostate cancer (CaP) is the most commonly diagnosed cancer and third leading cause of cancer-related death in North American males. Recent evidence suggests that androgens mediate disease progression as recurrent CaP tumors contain androgens in levels high enough to activate the androgen receptor (AR). We have previously shown that in the absence of exogenous androgens, CaP cells develop the ability to synthesize their own androgens. We hypothesize that a) androgens induce the in vitro expression and activity of cholesterol synthesis and esterification pathways and b) cholesterol synthesis, influx and efflux are altered in vivo to provide precursors for de novo androgen synthesis contributing to castration-resistant prostate cancer progression. METHODS: We have analyzed cholesterol metabolism in vitro (LNCaP, PC-3 and C4-2 cells in the presence of androgens) and in vivo (LNCaP xenograft model). The LNCaP xenograft model was used to mimic clinical progression of the disease. Tumors were excised from the same mouse at three stages: Androgen-Dependent (AD, prior to castration), Nadir (N, 8-days post castration) and Castration-Resistance (CRPC, 35-days post castration) and stored for further analysis. Protein expressions of AR, PSA and proteins involved in cholesterol synthesis and metabolism, influx and efflux as well as actin were determined by immunoblotting. Total cholesterol concentrations were determined within each excised tumor using a fluorescent assay and LC-MS. Tumoral steroid levels were assessed by LC-MS. RESULTS: Microsomal PC-3 and LNCaP cell HMG CoA reductase (cholesterol biosynthesis) activity was increased upon androgen treatment. ACAT1 activity (cholesterol esterification) was induced by androgens in PC-3 cells and this induction was AR- dependent as well as associated with increased ACAT1 protein expression. Tumor LDLr, SR-BI, HMG CoA reductase, ACAT1 and 2 as well as ABCA1 were altered during disease progression to CRPC likely to increase influx and synthesis of cholesterol. Total cholesterol levels increased in N and CRPC compared to AD. HMG CoA reductase expression was upregulated in N compared to AD (300%) and was maintained at this level at CRPC. Tumoral cholesterol biosynthesis ex vivo was increased from N to CRPC. Testosterone and dihydrosterone increased at CRPC to physiologically relevant levels and this may account for the increase in AR activation as determined by PSA expression at CRPC. CONCLUSIONS: Cellular cholesterol processes are altered by androgens and during progression to CRPC. Cholesterol from increased biosynthesis or uptake is likely a precursor for tumoral de novo androgen synthesis. ACKNOWLEDGEMENTS: Funding for this project was provided by the Canadian Institutes of Health Research (CIHR) and an NCIC-Terry Fox Group grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5096.