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Transcriptional suppression of androgen receptor by 18β-glycyrrhetinic acid in LNCaP human prostate cancer cells

Archives of Pharmacal Research 2020년 43권 4호 p.433 ~ 448
 ( Sun You ) - Wonkwang University Professional Graduate School of Oriental Medicine Department of Herbal Resources

 ( Jiang Min-Gyue ) - Wonkwang University Professional Graduate School of Oriental Medicine Department of Herbal Resources
 ( Park Pil-Hoon ) - College of Pharmacy Yeungnam University
 ( Song Kyung ) - Wonkwang University College of Pharmacy Department of Pharmacy

Abstract


Androgen receptor (AR) plays a pivotal role as a target for amplification/mutation in pathogenesis and tumor progression in prostate, and thus, controlling AR activity or expression might be a feasible therapeutic approach for the treatment of prostate cancer. Here, we report the novel mechanisms by which 18β-glycyrrhetinic acid (GA) targets AR to stimulate cell death in both hormone-responsive and -refractory prostate cancer cells. We found that miR-488, a tumor suppressive microRNA, was markedly induced by GA treatment, resulting in the down-regulation of AR expression and inhibition of cellular responses mediated by androgens. Moreover, GA not only suppressed the expression of androgen target genes (TMPRSS2, PSA, and NKX3.1), but also enhanced the suppressive effect of anti-androgens (bicalutamide and flutamide) on LNCaP cell growth. Our data further provides evidence that down-regulation of AR expression by GA may occur through transcriptional suppression at AR promoter region between ??1014 and ??829. Ectopic expression of SFR and E2F3α reversed the inhibitory effect of GA on AR promoter activity as well as protein expression, suggesting that GA may target transcription factors SRF and E2F3α to regulate AR expression. Taken together, our study provides new insights on AR regulation and GA as a potential therapeutic candidate for human prostate cancer.

키워드

Transcriptional suppression; Androgen receptor; 18β-glycyrrhetinic acid; miR-488; SRF; E2F3
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