Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p

被引：14

作者：

Barbier, Roberto H. ^{[1
]}

McCrea, Edel M. ^{[1
]}

Lee, Kristi Y. ^{[1
]}

Strope, Jonathan D. ^{[1
]}

Risdon, Emily N. ^{[1
]}

Price, Douglas K. ^{[1
]}

Chau, Cindy H. ^{[1
]}

Figg, William D. ^{[1
,2
]}

机构：

[1] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10,Room 5A03, Bethesda, MD 20892 USA

[2] NCI, Clin Pharmacol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

基金：

美国国家卫生研究院;

关键词：

TRANSPORTING POLYPEPTIDE 1B3; ANDROGEN RECEPTOR; GENE; TESTOSTERONE; RESISTANCE; INHIBITORS; MIR-181A-5P; CARCINOMA; PATHWAYS; SLCO2B1;

D O I：

10.1038/s41598-021-90143-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3 ' -untranslated region (3 ' UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3 ' UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p, indicating its potential role in upregulating SLCO1B3 expression. In this study, we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics.

引用

页数：11

共 53 条

[21] Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes [J].