Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer

Chengfei Liu, Wei Lou, Yezi Zhu, Joy C. Yang, Nagalakshmi Nadiminty, Nilesh W. Gaikwad, Christopher P Evans, Allen C Gao

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resen-sitized enzalutamide-resistant prostate cancer cells to enzalutamide treatmentboth in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.

Original languageEnglish (US)
Pages (from-to)1413-1422
Number of pages10
JournalCancer Research
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2015

Fingerprint

Androgens
Prostatic Neoplasms
MDV 3100
Indomethacin
Steroids
Dehydroepiandrosterone
Castration
Heterografts
Small Interfering RNA
Progesterone
Prostate
Neoplasms
Cholesterol
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. / Liu, Chengfei; Lou, Wei; Zhu, Yezi; Yang, Joy C.; Nadiminty, Nagalakshmi; Gaikwad, Nilesh W.; Evans, Christopher P; Gao, Allen C.

In: Cancer Research, Vol. 75, No. 7, 01.04.2015, p. 1413-1422.

Research output: Contribution to journalArticle

Liu, Chengfei ; Lou, Wei ; Zhu, Yezi ; Yang, Joy C. ; Nadiminty, Nagalakshmi ; Gaikwad, Nilesh W. ; Evans, Christopher P ; Gao, Allen C. / Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. In: Cancer Research. 2015 ; Vol. 75, No. 7. pp. 1413-1422.
@article{4e15b715a2c845d8b1e5515028966b1a,
title = "Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer",
abstract = "The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resen-sitized enzalutamide-resistant prostate cancer cells to enzalutamide treatmentboth in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.",
author = "Chengfei Liu and Wei Lou and Yezi Zhu and Yang, {Joy C.} and Nagalakshmi Nadiminty and Gaikwad, {Nilesh W.} and Evans, {Christopher P} and Gao, {Allen C}",
year = "2015",
month = "4",
day = "1",
doi = "10.1158/0008-5472.CAN-14-3080",
language = "English (US)",
volume = "75",
pages = "1413--1422",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer

AU - Liu, Chengfei

AU - Lou, Wei

AU - Zhu, Yezi

AU - Yang, Joy C.

AU - Nadiminty, Nagalakshmi

AU - Gaikwad, Nilesh W.

AU - Evans, Christopher P

AU - Gao, Allen C

PY - 2015/4/1

Y1 - 2015/4/1

N2 - The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resen-sitized enzalutamide-resistant prostate cancer cells to enzalutamide treatmentboth in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.

AB - The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resen-sitized enzalutamide-resistant prostate cancer cells to enzalutamide treatmentboth in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.

UR - http://www.scopus.com/inward/record.url?scp=84939279104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939279104&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-3080

DO - 10.1158/0008-5472.CAN-14-3080

M3 - Article

C2 - 25649766

AN - SCOPUS:84939279104

VL - 75

SP - 1413

EP - 1422

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 7

ER -