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PMID: 26797685 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Review

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression.

Hormones & cancer ·Vol. 7 ·No. 2 ·2016-04-00 ·Pages 104-13

Zhang A, Zhang J, Plymate S, Mostaghel EA

Abstract

Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

MeSH Terms
3-Hydroxyacyl CoA Dehydrogenases/genetics Animals Dihydrotestosterone/metabolism Disease Progression Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Glucuronosyltransferase/genetics,metabolism Humans Hydroxysteroid Dehydrogenases/genetics,metabolism Male Minor Histocompatibility Antigens/genetics,metabolism Prostatic Neoplasms/genetics,metabolism Prostatic Neoplasms, Castration-Resistant/genetics,metabolism Racemases and Epimerases/genetics,metabolism Receptors, Androgen/metabolism
Chemicals
AR protein, human Minor Histocompatibility Antigens Receptors, Androgen Dihydrotestosterone Hydroxysteroid Dehydrogenases 3-Hydroxyacyl CoA Dehydrogenases HSD17B10 protein, human AKR1C2 protein, human Glucuronosyltransferase UDP-glucuronosyltransferase 2B15, human UGT2B17 protein, human HSD17B6 protein, human Racemases and Epimerases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zhang Ailin
Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, MS D5-380, Seattle, WA, 98109, USA.
Zhang Jiawei
School of Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
Plymate Stephen
Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
Mostaghel Elahe A
Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, MS D5-380, Seattle, WA, 98109, USA. emostagh@fhcrc.org.
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Article Info
Journal
Hormones & cancer
Abbr.
Horm Cancer
ISSN
1868-8500
DOI
10.1007/s12672-016-0250-9
Email
emostagh@fhcrc.org
Published
2016-04-00
Epub
2016-00-21
Pages
104-13
Language
English
Region
United States
NLM ID
101518427
PMCID
PMC4859429
Subset
IM
Grants
NCI NIH HHS · P50 CA097186 · United States
NCI NIH HHS · P50 CA97186 · United States
External Links
PubMed source DOI: 10.1007/s12672-016-0250-9 PMC Full Text
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