Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer

Chengfei Liu, Cameron M. Armstrong, Wei Lou, Alan Lombard, Christopher P Evans, Allen C Gao

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 resensitizes resistant cells to abiraterone treatment. In abiraterone-resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone-resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)35-44
Number of pages10
JournalMolecular Cancer Therapeutics
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2017

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Androgens
Prostatic Neoplasms
Androgen Receptors
Indomethacin
abiraterone
Down-Regulation
Clinical Trials
Recurrence
Enzymes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. / Liu, Chengfei; Armstrong, Cameron M.; Lou, Wei; Lombard, Alan; Evans, Christopher P; Gao, Allen C.

In: Molecular Cancer Therapeutics, Vol. 16, No. 1, 01.01.2017, p. 35-44.

Research output: Contribution to journalArticle

Liu, Chengfei ; Armstrong, Cameron M. ; Lou, Wei ; Lombard, Alan ; Evans, Christopher P ; Gao, Allen C. / Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 1. pp. 35-44.
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