caa a22 4500 445312890 CHVBK 20180317142636.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s11095-010-0210-y doi (NATIONALLICENCE)springer-10.1007/s11095-010-0210-y Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer [Elektronische Daten] [Alexis Twiddy, Carlos Leon, Kishor Wasan] 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. Springer Science+Business Media, LLC, 2010 castration resistant prostate cancer nationallicence cholesterol nationallicence novel therapeutics targets nationallicence statins nationallicence scavenger receptor class B type I nationallicence ABCA1 : ATP-binding cassette transporter-subfamily A1 nationallicence ACAT : acyl-coenzyme A:cholesterol acyltransferase nationallicence ADT : androgen deprivation therapy nationallicence AKR1C1/2/3 : aldo-keto reductase family 1 members C1/2/3 nationallicence AR : androgen Receptor nationallicence C4-2 : castration-resistant cell line derived from LNCaP nationallicence CaP : prostate cancer nationallicence CE : cholesteryl ester nationallicence CRPC : castration-resistant Prostate Cancer nationallicence DHT : dihydrotestosterone nationallicence DU145 : castration-resistant prostate cancer carcinoma cell line derived from brain metastases nationallicence HDL : high-density lipoprotein nationallicence HMGCR : 3-hydroxy-3-methylglutaryl-Coenzyme A reductase nationallicence HSD17B3 : 17β-Hydroxy steroid dehydrogenase 3 nationallicence HSL : hormone-sensitive lipase nationallicence LDL : low-density lipoprotein nationallicence LNCaP : lymph node metastatic prostate adenocarcinoma cell line nationallicence PC-3 : bone-derived castration-resistant cell line nationallicence SR-BI : scavenger Receptor Class B Type I nationallicence SRD5A1 : steroid 5α-reductase Type 1 nationallicence StAR : steroidogenic acute regulatory protein nationallicence Twiddy Alexis Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut Leon Carlos Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut Wasan Kishor Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 423-437 0724-8741 28:3<423 2011 28 11095 https://doi.org/10.1007/s11095-010-0210-y text/html Onlinezugriff via DOI 1 review-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0210-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Twiddy Alexis Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut NATIONALLICENCE 700 1- Leon Carlos Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut NATIONALLICENCE 700 1- Wasan Kishor Division of Pharmaceutics and Biopharmaceutics Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, V6T 1Z3, Vancouver, British Columbia, Canada aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 423-437 0724-8741 28:3<423 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer