White button mushroom (Agaricus bisporus) disrupts androgen receptor signaling in human prostate cancer cells and patient-derived xenograft |
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| Institution: | 1. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA;2. School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA;3. Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA;4. Department of Radiation Oncology, Tufts University, Boston, MA, USA;1. Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China;2. Clinical Laboratory, Affiliated Hospital of Qingdao University, Qingdao, China;1. Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan;2. Department of Immunology, Faculty of Medicine, Yamagata University, Yamagata, Japan;3. Department of Pathological Diagnostics, Faculty of Medicine, Yamagata University, Yamagata, Japan;4. Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan;5. AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan;6. Miyata Diabetes and Metabolism Clinic, Fukushima-ku, Osaka, Japan;1. Research Center of the CHU de Québec, CHUL, 2705, Boulevard Laurier, Quebec City, G1V 4G2, Canada;2. Department of Molecular Medicine, Faculty of Medicine, Laval University, 1050, Avenue de la Médecine, Quebec City, G1V OA6, Canada;3. Centre des Maladie du Sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050, Chemin Sainte-Foy, Quebec City, G1S 4L8, Canada;4. Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, 1050, Avenue de la Médecine, Quebec City, G1V OA6, Canada;5. Department of Surgery, Faculty of Medicine, Laval University, 1050, Avenue de la Médecine, Quebec City, G1V OA6, Canada |
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| Abstract: | White button mushroom (WBM) (Agaricus bisporus) is a potential prostate cancer (PCa) chemo-preventative and therapeutic agent. Our clinical phase ? trial of WBM powder in patients with biochemically recurrent PCa indicated that WBM intake reduced the circulating levels of prostate-specific antigen (PSA). We hypothesized that WBM exerts its effects on PCa through the androgen receptor (AR) signaling axis. Therefore, we conducted a reverse translational study with androgen-dependent PCa cell lines (LNCaP and VCaP) and patient-derived-xenografts (PDX) from a prostate tumor (TM00298). In both LNCaP and VCaP cells, western blots and qRT-PCR assays indicated that WBM extract (6–30 mg/mL) suppressed DHT-induced PSA expression and cell proliferation in a dose-dependent manner. Immunofluorescence analysis of AR revealed that WBM extract interrupted the AR nuclear-cytoplasmic distribution. PSA promotor-luciferase assay suggested that WBM extract inhibited DHT-induced luciferase activity. RNA-Seq on WBM-treated LNCaP cells confirmed that WBM treatment suppressed the androgen response pathways and cell-cycle control pathways. Our PDX showed that oral intake of WBM extract (200 mg/kg/d) suppressed tumor growth and decreased PSA levels in both tumors and serum. In the present study, we also identified a conjugated linoleic acid isomer (CLA-9Z11E) as a strong AR antagonist by performing LanthaScreen TR-FRET AR Coactivator Interaction Assays. The inhibitory effect of CLA-9Z11E (IC50: 350 nM) was nearly two times stronger than the known AR antagonist, cyproterone acetate (IC50: 672 nM). The information gained from this study improves the overall understanding of how WBM may contribute to the prevention and treatment of PCa. |
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