Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3

Xiaoping Yu; Jiali Yan; Yulu Li; Jing Chen; Lujie Zheng; Tianyu Fu; Yanfeng Zhu

doi:10.29219/fnr.v67.9024

Xiaoping Yu School of Medicine and Nursing, Chengdu University, Chengdu, China
Jiali Yan School of Public Health, Chengdu Medical College, Chengdu, China
Yulu Li National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
Jing Chen School of Public Health, Chengdu Medical College, Chengdu, China
Lujie Zheng School of Public Health, Chengdu Medical College, Chengdu, China
Tianyu Fu School of Public Health, Chengdu Medical College, Chengdu, China
Yanfeng Zhu School of Public Health, Chengdu Medical College, Chengdu, China

DOI: https://doi.org/10.29219/fnr.v67.9024

Keywords: Genistein; castration-resistant prostate cancer; AKR1C3; Prostate cancer

Abstract

Background: Prostate cancer is the second leading cause of cancer-related death among males in America. The patients’ survival time is significantly reduced after prostate cancer develops into castration-resistant prostate cancer (CRPC). It has been reported that AKR1C3 is involved in this progression, and that its abnormal expression is directly correlated with the degree of CRPC malignancy. Genistein is one of the active components of soy isoflavones, and many studies have suggested that it has a better inhibitory effect on CRPC.

Objective: This study aimed to investigate the antitumor effect of genistein on CRPC and the potential mechanism of action.

Design: A xenograft tumor mouse model established with 22RV1 cells was divided into the experimental group and the control group, and the former was given 100 mg/kg.bw/day of genistein, with 22RV1, VCaP, and RWPE-1 cells cultured in a hormone-free serum environment and treated with different concentrations of genistein (0, 12.5, 25, 50, and 100 μmol/L) for 48 h. Molecular docking was used to elucidate the molecular interactions between genistein and AKR1C3.

Results: Genistein inhibits CRPC cell proliferation and in vivo tumorigenesis. The western blot analysis confirmed that the genistein significantly inhibited prostate-specific antigen production in a dose-dependent manner. In further results, AKR1C3 expression was decreased in both the xenograft tumor tissues and the CRPC cell lines following genistein gavage feeding compared to the control group, with the reduction becoming more obvious as the concentration of genistein was increased. When the genistein was combined with AKR1C3 small interfering ribonucleic acid and an AKR1C3 inhibitor (ASP-9521), the inhibitory effect on the AKR1C3 was more pronounced. In addition, the molecular docking results suggested that the genistein had a strong affinity with the AKR1C3, and that it could be a promising AKR1C3 inhibitor.

Conclusion: Genistein inhibits the progression of CRPC via the suppression of AKR1C3.

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