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Pharmaceutical Research

, Volume 28, Issue 3, pp 423–437 | Cite as

Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

  • Alexis L. Twiddy
  • Carlos G. Leon
  • Kishor M. WasanEmail author
Expert Review

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.

KEY WORDS

castration resistant prostate cancer cholesterol novel therapeutics targets statins scavenger receptor class B type I 

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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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alexis L. Twiddy
    • 1
  • Carlos G. Leon
    • 1
  • Kishor M. Wasan
    • 1
    Email author
  1. 1.Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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