Format

Send to

Choose Destination
Oncotarget. 2015 May 10;6(13):11600-13.

Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity.

Yun H1,2, Xie J1,3, Olumi AF4, Ghosh R1,2,5,6, Kumar AP1,2,5,6,7.

Author information

1
Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.
2
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
3
Department of Urology, Shanxi Dayi Hospital, Shanxi Academy of Medical Science, Taiyuan, P.R.China.
4
Department of Urology, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA.
5
Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
6
Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.
7
South Texas Veterans Health Care System, San Antonio, TX, USA.

Abstract

We provide first-time evidence for ERβ-mediated transcriptional upregulation of c-FLIP as an underlying mechanism in the development of castrate-resistant cancer. While androgens inhibit apoptosis partly through transcriptional upregulation of the anti-apoptotic protein, c-FLIP in androgen-responsive cells, they downregulate c-FLIP in androgen-independent cells. We found that although Sp1 and p65 trans-activate c-FLIP, the combination of Sp1 and p65 has differential effects in a cellular context-dependent manner. We show that activation of the androgen metabolism enzyme, aldo-keto reductase, AKR1C1, relieves androgen independence through activation of 3β-Adiol-mediated upregulation of ERβ. ERβ competes with Sp1 and Sp3 to transcriptionally downregulate c-FLIP in the absence of consensus estrogen-response element in androgen-independent cells. Forced expression of AR in androgen-independent cells show that ERβ-mediated growth inhibition occurs under conditions of androgen independence. Reactivation of ERβ with the estrogenic metabolite, 2-methoxyestradiol, decreased enrichment ratio of Sp1/Sp3 at the c-FLIP promoter with concomitant effects on cell growth and death. Expression of Sp1 and c-FLIP are elevated while AKR1C1, ERβ and Sp3 are significantly low in human prostate tumor samples. ERβ is epigenetically silenced in prostate cancer patients, therefore our results suggest that combination of ERβ agonists with ADT would benefit men stratified on the basis of high estrogen levels.

KEYWORDS:

2-methoxyestradiol; androgen receptor; c-FLIP; estrogen receptor beta; transcription factor

PMID:
25816367
PMCID:
PMC4484479
DOI:
10.18632/oncotarget.3417
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center