Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity
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Huiyoung Yun1,2,*, Jianping Xie1,7,*, Aria F. Olumi3, Rita Ghosh1,2,4,5, Addanki P. Kumar1,2,4,5,6
1Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA
2Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA
3Department of Urology, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA
4Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA
5Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA
6South Texas Veterans Health Care System, San Antonio, TX, USA
7Department of Urology, Shanxi Dayi Hospital, Shanxi Academy of Medical Science, Taiyuan, P.R., China
*These authors have contributed equally to this work
Addanki P. Kumar, e-mail: [email protected]
Keywords: androgen receptor, estrogen receptor beta, c-FLIP, 2-methoxyestradiol, transcription factor
Received: January 28, 2015 Accepted: February 19, 2015 Published: March 24, 2015
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.
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