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Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

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ABSTRACT

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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Abbreviations

ABCA1:

ATP-binding cassette transporter-subfamily A1

ACAT:

acyl-coenzyme A:cholesterol acyltransferase

ADT:

androgen deprivation therapy

AKR1C1/2/3:

aldo-keto reductase family 1 members C1/2/3

AR:

androgen Receptor

C4-2:

castration-resistant cell line derived from LNCaP

CaP:

prostate cancer

CE:

cholesteryl ester

CRPC:

castration-resistant Prostate Cancer

DHT:

dihydrotestosterone

DU145:

castration-resistant prostate cancer carcinoma cell line derived from brain metastases

HDL:

high-density lipoprotein

HMGCR:

3-hydroxy-3-methylglutaryl-Coenzyme A reductase

HSD17B3:

17β-Hydroxy steroid dehydrogenase 3

HSL:

hormone-sensitive lipase

LDL:

low-density lipoprotein

LNCaP:

lymph node metastatic prostate adenocarcinoma cell line

PC-3:

bone-derived castration-resistant cell line

SR-BI:

scavenger Receptor Class B Type I

SRD5A1:

steroid 5α-reductase Type 1

StAR:

steroidogenic acute regulatory protein

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  1. Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, Vancouver, British Columbia, Canada , V6T 1Z3

    Alexis L. Twiddy, Carlos G. Leon & Kishor M. Wasan

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Twiddy, A.L., Leon, C.G. & Wasan, K.M. Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer. Pharm Res 28, 423–437 (2011). https://doi.org/10.1007/s11095-010-0210-y

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