Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells In‑Sung Song1 · Yu Jeong Jeong1,2 · Jueun Kim1,2 · Kyoung‑Hwa Seo4 · Nam‑In Baek4 · Yunlim Kim5 · Choung‑Soo Kim5 · Sung‑Wuk Jang1,2,3 Received: 24 July 2019 / Revised: 27 November 2019 / Accepted: 18 December 2019 © Springer Nature Switzerland AG 2020
Abstract The androgen receptor (AR) plays an important role in the pathogenesis and development of prostate cancer (PCa). Mostly, PCa progresses to androgen-independent PCa, which has activated AR signaling from androgen-dependent PCa. Thus, inhibition of AR signaling may be an important therapeutic target in androgen-dependent and castration-resistant PCa. In this study, we determined the anticancer effect of a newly found natural compound, sakurasosaponin (S-saponin), using androgendependent and castration-resistant PCa cell lines. S-saponin induces mitochondrial-mediated cell death in both androgendependent (LNCaP) and castration-resistant (22Rv1 and C4-2) PCa cells, via AR expression. S-saponin treatment induces a decrease in AR expression in a time- and dose-dependent manner and a potent decrease in the expression of its target genes, including prostate-specific antigen (PSA), transmembrane protease, serin 2 (TMPRSS2), and NK3 homeobox 1 (NKX3.1). Furthermore, S-saponin treatment decreases B-cell lymphoma-extra large (Bcl-xL) and mitochondrial membrane potential, thereby increasing the release of cytochrome c into the cytosol. Moreover, Bcl-xL inhibition and subsequent mitochondriamediated cell death caused by S-saponin were reversed by Bcl-xL or AR overexpression. Interestingly, S-saponin-mediated cell death was significantly reduced by a reactive oxygen species (ROS) scavenger, N-acetylcystein. Animal xenograft experiments showed that S-saponin treatment significantly reduced tumor growth of AR-positive 22Rv1 xenografts but not AR-negative PC-3 xenografts. Taken together, for the first time, our results revealed that S-saponin induces mitochondrialmediated cell death in androgen-dependent and castration-resistant cells through regulation of AR mechanisms, including downregulation of Bcl-xL expression and induction of ROS stress by decreasing mitochondrial membrane potential. Keywords Prostate cancer · Sakurasosaponin · Androgen receptor · Bcl-xL
Introduction In-Sung Song and Yu Jeong Jeong contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03429-2) contains supplementary material, which is available to authorized users. * Choung‑Soo Kim [email protected] * Sung‑Wuk Jang [email protected] 1
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138‑736, Republic of Korea
Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul 138‑736, Republic of Korea
2
Prostate cancer (PCa) is
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