title: Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity.
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.
authors: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors: Huiyoung
authors: H
authors: Yun
authors: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Urology, Shanxi Dayi Hospital, Shanxi Academy of Medical Science, Taiyuan, P.R.China.
authors: Jianping
authors: J
authors: Xie
authors: Department of Urology, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA.
authors: Aria F
authors: AF
authors: Olumi
authors: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.
authors: Rita
authors: R
authors: Ghosh
authors: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.|South Texas Veterans Health Care System, San Antonio, TX, USA.
authors: Addanki P
authors: AP
authors: Kumar
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000726:Androgen Antagonists / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal; D017209:Apoptosis; D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D004967:Estrogens; C498143:RELA protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D051996:Transcription Factor RelA; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
keywords: 2-methoxyestradiol; androgen receptor; c-FLIP; estrogen receptor beta; transcription factor