FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A

S. Periyasamy, T. Hinds, L. Shemshedini, Weinian Shou, E. R. Sanchez

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.

Original languageEnglish
Pages (from-to)1691-1701
Number of pages11
JournalOncogene
Volume29
Issue number11
DOIs
StatePublished - Mar 2010

Fingerprint

Tacrolimus
Cyclosporine
Androgens
Prostatic Neoplasms
Androgen Receptors
Growth
Cell Proliferation
Genes
Ligands
Small Interfering RNA
Proteins
Cell Line

Keywords

  • Androgen receptor
  • Cyp40
  • FKBP51
  • FKBP52
  • Prostate cancer
  • Transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. / Periyasamy, S.; Hinds, T.; Shemshedini, L.; Shou, Weinian; Sanchez, E. R.

In: Oncogene, Vol. 29, No. 11, 03.2010, p. 1691-1701.

Research output: Contribution to journalArticle

Periyasamy, S. ; Hinds, T. ; Shemshedini, L. ; Shou, Weinian ; Sanchez, E. R. / FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. In: Oncogene. 2010 ; Vol. 29, No. 11. pp. 1691-1701.
@article{b07306f2951b4153bcd4e402b352e897,
title = "FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A",
abstract = "Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.",
keywords = "Androgen receptor, Cyp40, FKBP51, FKBP52, Prostate cancer, Transcription",
author = "S. Periyasamy and T. Hinds and L. Shemshedini and Weinian Shou and Sanchez, {E. R.}",
year = "2010",
month = "3",
doi = "10.1038/onc.2009.458",
language = "English",
volume = "29",
pages = "1691--1701",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A

AU - Periyasamy, S.

AU - Hinds, T.

AU - Shemshedini, L.

AU - Shou, Weinian

AU - Sanchez, E. R.

PY - 2010/3

Y1 - 2010/3

N2 - Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.

AB - Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.

KW - Androgen receptor

KW - Cyp40

KW - FKBP51

KW - FKBP52

KW - Prostate cancer

KW - Transcription

UR - http://www.scopus.com/inward/record.url?scp=77949654801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949654801&partnerID=8YFLogxK

U2 - 10.1038/onc.2009.458

DO - 10.1038/onc.2009.458

M3 - Article

C2 - 20023700

AN - SCOPUS:77949654801

VL - 29

SP - 1691

EP - 1701

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 11

ER -