From transforming growth factor-β signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells

doi:10.1073/pnas.061305498

From transforming growth factor-β signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells

George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and Cancer Center, University of Rochester Medical Center, Rochester, NY 14642; and Reproductive Medicine Institute, Chang Gung University, Kaohsiung, Taiwan

Edited by Michael G. Rosenfeld, University of California at San Diego, La Jolla, CA, and approved January 8, 2001 (received for review June 30, 2000)

Abstract

Although transforming growth factor-β (TGF-β) has been identified to mainly inhibit cell growth, the correlation of elevated TGF-β with increasing serum prostate-specific antigen (PSA) levels in metastatic stages of prostate cancer has also been well documented. The molecular mechanism for these two contrasting effects of TGF-β, however, remains unclear. Here we report that Smad3, a downstream mediator of the TGF-β signaling pathway, functions as a coregulator to enhance androgen receptor (AR)-mediated transactivation. Compared with the wild-type AR, Smad3 acts as a strong coregulator in the presence of 1 nM 5α-dihydrotestosterone, 10 nM 17β-estradiol, or 1 μM hydroxyflutamide for the LNCaP mutant AR (mtAR T877A), found in many prostate tumor patients. We further showed that endogenous PSA expression in LNCaP cells can be induced by 5α-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression. Together, our findings establish Smad3 as an important coregulator for the androgen-signaling pathway and provide a possible explanation for the positive role of TGF-β in androgen-promoted prostate cancer growth.

Footnotes

↵ * To whom reprint requests should be addressed. E-mail: chang{at}urmc.rochester.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

AR,

androgen receptor;

TGF-β,

transforming growth factor β;

TβRI,

TGF-β receptor type I;

TβRII,

TGF-β receptor type II;

wtAR,

wild-type androgen receptor;

mtAR,

mutant AR;

ARA,

androgen receptor associated protein;

DHT,

5α-dihydrotestosterone;

E2,

17β-estradiol;

HF,

hydroxyflutamide;

DBD,

DNA-binding domain;

LBD,

ligand-binding domain;

PSA,

prostate-specific antigen;

CAT,

chloramphenicol acetyltransferase;

GST,

glutathione S-transferase;

VDR,

vitamin D receptor;

ARE,

androgen response element;

MMTV,

mouse mammary tumor virus