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

Huiyoung Yun, Jianping Xie, Aria F. Olumi, Rita Ghosh, Addanki P. Kumar

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 transactivate 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 estrogenresponse element in androgen-independent cells. Forced expression of AR in androgenindependent 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.

Original languageEnglish (US)
Pages (from-to)11600-11613
Number of pages14
JournalOncotarget
Volume6
Issue number13
DOIs
StatePublished - 2015

Keywords

  • 2-methoxyestradiol
  • Androgen receptor
  • Estrogen receptor beta
  • Transcription factor
  • c-FLIP

ASJC Scopus subject areas

  • Oncology

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