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

Horm Cancer. 2016 Apr;7(2):104-13. doi: 10.1007/s12672-016-0250-9. Epub 2016 Jan 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / genetics
  • Animals
  • Dihydrotestosterone / metabolism*
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hydroxysteroid Dehydrogenases / genetics
  • Hydroxysteroid Dehydrogenases / metabolism
  • Male
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Racemases and Epimerases / genetics
  • Racemases and Epimerases / metabolism
  • Receptors, Androgen / metabolism*

Substances

  • 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