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

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


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/ 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.


Download data is not yet available.


Atan A, Tuncel A, Yesil S, Balbay D. Serum testosterone level, testosterone replacement treatment, and prostate cancer. Adv Urol 2013; 2013: 275945. doi: 10.1155/2013/275945

Bahmad HF, Samman H, Monzer A, Hadadeh O, Cheaito K, Abdel-Samad R, et al. The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem-like cells. Mol Carcinog 2019; 58(7): 1208–20. doi: 10.1002/mc.23004

Sivonova MK, Kaplan P, Tatarkova Z, Lichardusova L, Dusenka R, Jurecekova J. Androgen receptor and soy isoflavones in prostate cancer. Mol Clin Oncol 2019; 10(2): 191–204. doi: 10.3892/mco.2018.1792

Mansinho A, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets and treatment. Adv Exp Med Biol 2018; 1096: 117–33. doi: 10.1007/978-3-319-99286-0_7

Sanchez BG, Bort A, Mateos-Gomez PA, Rodriguez-Henche N, Diaz-Laviada I. Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase. Cancer Cell Int 2019; 19: 54. doi: 10.1186/s12935-019-0769-2

Zheng X, Jiang Z, Li X, Zhang C, Li Z, Wu Y, et al. Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors. Bioorg Med Chem 2018; 26(22): 5934–43. doi: 10.1016/j.bmc.2018.10.044

Prelaj A, Rebuzzi SE, Buzzacchino F, Pozzi C, Ferrara C, Frantellizzi V, et al. Radium-223 in patients with metastatic castration-resistant prostate cancer: efficacy and safety in clinical practice. Oncol Lett 2019; 17(2): 1467–76. doi: 10.3892/ol.2018.9785

Swami U, McFarland TR, Nussenzveig R, Agarwal N. Advanced prostate cancer: treatment advances and future directions. Trends Cancer 2020; 6(8): 702–15. doi: 10.1016/j.trecan.2020.04.010

Pfeiffer MJ, Smit FP, Sedelaar JP, Schalken JA. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer. Mol Med 2011; 17(7–8): 657–64. doi: 10.2119/molmed.2010.00143

Li G, Zhu Y, Zhang Y, Lang J, Chen Y, Ling W. Estimated daily flavonoid and stilbene intake from fruits, vegetables, and nuts and associations with lipid profiles in Chinese adults. J Acad Nutr Diet 2013; 113(6): 786–94. doi: 10.1016/j.jand.2013.01.018

Ionescu VS, Popa A, Alexandru A, Manole E, Neagu M, Pop S. Dietary phytoestrogens and their metabolites as epigenetic modulators with impact on human health. Antioxidants (Basel) 2021; 10(12): 1893. doi: 10.3390/antiox10121893

Li F, Zhu Y, Chen J, Zhou J, He Y, Yu X. Geinsten inhibits the proliferation of VCaP castration-resistant prostate cancer cells. Zhonghua Nan Ke Xue 2016; 22(12): 1065–7.

Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, Clinton SK. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 1999; 129(9): 1628–35. doi: 10.1093/jn/129.9.1628

Pavese JM, Krishna SN, Bergan RC. Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis. Am J Clin Nutr 2014; 100 Suppl 1: 431S–6S. doi: 10.3945/ajcn.113.071290

Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto CH, Helenowski I, et al. Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 2008; 68(6): 2024–32. doi: 10.1158/0008-5472.CAN-07-1246

Filella X, Foj L. Prostate cancer detection and prognosis: from prostate specific antigen (PSA) to exosomal biomarkers. Int J Mol Sci 2016; 17(11): 1784. doi: 10.3390/ijms17111784

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008; 68(11): 4447–54. doi: 10.1158/0008-5472.CAN-08-0249

Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006; 66(5): 2815–25. doi: 10.1158/0008-5472.CAN-05-4000

Hofland J, van Weerden WM, Dits NF, Steenbergen J, van Leenders GJ, Jenster G, et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res 2010; 70(3): 1256–64. doi: 10.1158/0008-5472.CAN-09-2092

Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reductases and cancer. Ann N Y Acad Sci 2009; 1155: 33–42. doi: 10.1111/j.1749-6632.2009.03700.x

Adeniji AO, Chen M, Penning TM. AKR1C3 as a target in castrate resistant prostate cancer. J Steroid Biochem Mol Biol 2013; 137: 136–49. doi: 10.1016/j.jsbmb.2013.05.012

Li C, Zhao Y, Zheng X, Zhang H, Zhang L, Chen Y, et al. In vitro CAPE inhibitory activity towards human AKR1C3 and the molecular basis. Chem Biol Interact 2016; 253: 60–5. doi: 10.1016/j.cbi.2016.05.012

Kafka M, Mayr F, Temml V, Moller G, Adamski J, Hofer J, et al. Dual inhibitory action of a novel AKR1C3 inhibitor on both full-length AR and the variant AR-V7 in enzalutamide resistant metastatic castration resistant prostate cancer. Cancers (Basel) 2020; 12(8): 2092. doi: 10.3390/cancers12082092

Endo S, Oguri H, Segawa J, Kawai M, Hu D, Xia S, et al. Development of novel AKR1C3 inhibitors as new potential treatment for castration-resistant prostate cancer. J Med Chem 2020; 63(18): 10396–411. doi: 10.1021/acs.jmedchem.0c00939

Zhou M, Wang X, Xia J, Cheng Y, Xiao L, Bei Y, et al. A mansonone derivative coupled with monoclonal antibody 4D5-modified chitosan inhibit AKR1C3 to treat castration-resistant prostate cancer. Int J Nanomedicine 2020; 15: 3087–98. doi: 10.2147/IJN.S241324

Mukund V, Mukund D, Sharma V, Mannarapu M, Alam A. Genistein: its role in metabolic diseases and cancer. Crit Rev Oncol Hematol 2017; 119: 13–22. doi: 10.1016/j.critrevonc.2017.09.004

Barnes S, Peterson TG, Coward L. Rationale for the use of genistein- containing soy matrices in chemoprevention trials for breast and prostate cancer. J Cell Biochem 1995; 22: 181–7. doi: 10.1002/jcb.240590823

Dastjerdi MN, Kavoosi F, Valiani A, Esfandiari E, Sanaei M, Sobhanian S, et al. Inhibitory effect of genistein on PLC/PRF5 hepatocellular carcinoma cell line. Int J Prev Med 2015; 6: 54. doi: 10.4103/2008-7802.158914

Kang NH, Shin HC, Oh S, Lee KH, Lee YB, Choi KC. Soy milk digestion extract inhibits progression of prostate cancer cell growth via regulation of prostate cancerspecific antigen and cell cycle-regulatory genes in human LNCaP cancer cells. Mol Med Rep 2016; 14(2): 1809–16. doi: 10.3892/mmr.2016.5408

Lazarevic B, Boezelijn G, Diep LM, Kvernrod K, Ogren O, Ramberg H, et al. Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial. Nutr Cancer 2011; 63(6): 889–98. doi: 10.1080/01635581.2011.582221

Liu C, Armstrong CM, Lou W, Lombard A, Evans CP, Gao AC. Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol Cancer Ther 2017; 16(1): 35–44. doi: 10.1158/1535-7163.MCT-16-0186
How to Cite
Yu X., Yan J., Li Y., Chen J., Zheng L., Fu T., & Zhu Y. (2023). Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3. Food & Nutrition Research, 67.
Original Articles