Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

Kai Hsiung Chang, Rui Li, Mahboubeh Papari-Zareei, Lori Watumull, Yan Daniel Zhao, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)13728-13733
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number33
DOIs
StatePublished - Aug 16 2011

Fingerprint

Dihydrotestosterone
Castration
Testosterone
Prostatic Neoplasms
Isoenzymes
Steroids
Oxidoreductases
Androgens
Androstenedione
Metabolic Networks and Pathways
Heterografts
Prostate
Neoplasms
Neoplasm Metastasis
Cell Line
Therapeutics

Keywords

  • 5-alpha-androstanedione
  • Abiraterone acetate
  • Hormonal therapy
  • Hormone resistance
  • Tumor metabolism

ASJC Scopus subject areas

  • General

Cite this

Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. / Chang, Kai Hsiung; Li, Rui; Papari-Zareei, Mahboubeh; Watumull, Lori; Zhao, Yan Daniel; Auchus, Richard J.; Sharifi, Nima.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 33, 16.08.2011, p. 13728-13733.

Research output: Contribution to journalArticle

Chang, Kai Hsiung ; Li, Rui ; Papari-Zareei, Mahboubeh ; Watumull, Lori ; Zhao, Yan Daniel ; Auchus, Richard J. ; Sharifi, Nima. / Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 33. pp. 13728-13733.
@article{003a8ec053914aa98d924ea552f72473,
title = "Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer",
abstract = "In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.",
keywords = "5-alpha-androstanedione, Abiraterone acetate, Hormonal therapy, Hormone resistance, Tumor metabolism",
author = "Chang, {Kai Hsiung} and Rui Li and Mahboubeh Papari-Zareei and Lori Watumull and Zhao, {Yan Daniel} and Auchus, {Richard J.} and Nima Sharifi",
year = "2011",
month = "8",
day = "16",
doi = "10.1073/pnas.1107898108",
language = "English (US)",
volume = "108",
pages = "13728--13733",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

TY - JOUR

T1 - Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

AU - Chang, Kai Hsiung

AU - Li, Rui

AU - Papari-Zareei, Mahboubeh

AU - Watumull, Lori

AU - Zhao, Yan Daniel

AU - Auchus, Richard J.

AU - Sharifi, Nima

PY - 2011/8/16

Y1 - 2011/8/16

N2 - In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

AB - In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

KW - 5-alpha-androstanedione

KW - Abiraterone acetate

KW - Hormonal therapy

KW - Hormone resistance

KW - Tumor metabolism

UR - http://www.scopus.com/inward/record.url?scp=80051963331&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051963331&partnerID=8YFLogxK

U2 - 10.1073/pnas.1107898108

DO - 10.1073/pnas.1107898108

M3 - Article

C2 - 21795608

AN - SCOPUS:80051963331

VL - 108

SP - 13728

EP - 13733

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 33

ER -