White Button Mushroom Disrupts AR Signaling in Prostate Cancer: The Scientific Basis for a Diet-Based Chemoprevention

Abstract White button mushroom (WBM) (Agaricus bisporus) is a potential prostate cancer (PCa) chemo-preventive 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), with minimal side effects [1]. We hypothesized that WBM exerts its effects on PCa through the androgen receptor (AR) signaling axis. We thus conducted the reverse translational study. Androgen-sensitive PCa cell lines (LNCaP and VCaP) and patient-derived-xenografts (PDX), of a prostate tumor (TM00298) were used. 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 on AR revealed that the nuclear localization of AR was reduced upon WBM extract treatment, which agreed with the results of a PSA promotor-luciferase assay, suggesting that WBM extract inhibited DHT-induced luciferase activity. RNA-Seq on WBM-treated LNCaP cells confirmed that WBM treatment suppressed androgen response pathways and cell-cycle control pathways. Our prostate cancer PDX showed that oral intake of WBM extract (200 mg/kg/day) significantly suppressed tumor growth, as well as decreased PSA levels in both tumors and serum. Both in vitro and in vivo studies suggested that chemical(s) in WBM extract behave as AR antagonist(s). We previously identified a conjugated linoleic acid isomer (CLA-9Z11E) as an active component in WBM extract. In the present study, we extended these findings by performing LanthaScreen™ TR-FRET AR Coactivator Interaction Assays for a direct interaction of CLA-9Z11E with AR. We report here that CLA-9Z11E exerts a strong antagonist potency against the recruitment of an AR coactivator peptide towards AR. 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. It also serves as an important, scientific basis for developing diet-based chemoprevention and integrative therapeutic strategies for prostate cancer (supported by NIH R01 CA227230). Reference: [1] Twardowski P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer. 2015.121(17):2942-50.

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A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus -induced prostate-specific antigen responses

Cancer ◽

10.1002/cncr.29421 ◽

2015 ◽

Vol 121 (17) ◽

pp. 2942-2950 ◽

Cited By ~ 16

Author(s):

Przemyslaw Twardowski ◽

Noriko Kanaya ◽

Paul Frankel ◽

Timothy Synold ◽

Christopher Ruel ◽

...

Keyword(s):

Prostate Cancer ◽

Phase I ◽

Prostate Specific Antigen ◽

Agaricus Bisporus ◽

Phase I Trial ◽

Specific Antigen ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Recurrent Prostate Cancer

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Regulation of prostate-specific antigen by activin A in prostate cancer LNCaP cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00443.2003 ◽

2004 ◽

Vol 286 (6) ◽

pp. E927-E931 ◽

Cited By ~ 22

Author(s):

Yasuhisa Fujii ◽

Satoru Kawakami ◽

Yohei Okada ◽

Yukio Kageyama ◽

Kazunori Kihara

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Androgen Receptor ◽

Cell Growth ◽

Prostate Specific Antigen ◽

Specific Antigen ◽

Activin A ◽

Prostate Tissue ◽

Dependent Manner ◽

Lncap Cells

Activins are multifunctional growth and differentiation factors and stimulate FSH-β gene expression and FSH secretion by the pituitary gonadotropes. Follistatins bind activin, resulting in the neutralization of activin bioactivity. The activin/follistatin system is present in the prostate tissue. Prostate-specific antigen (PSA) plays an important role in male reproductive physiology as well as being very important as a tumor marker for prostate cancer. Thus the regulation of PSA has important clinical implications. Previous studies showed that PSA is primarily regulated by androgens. In the present study, we evaluated the direct effects of activin A on the proliferation and PSA production of prostate cancer LNCaP cells, which express functional activin receptors and androgen receptor and PSA. LNCaP cells were treated with activin A and 5α-dihydrotestosterone (DHT) with or without their antagonists (follistatin or the nonsteroidal anti-androgen bicalutamide). Activin A decreased cell growth of LNCaP cells in a dose-dependent manner, whereas DHT increased it in a biphasic manner. In contrast to their opposing actions on cell growth, both activin A and DHT upregulated PSA gene expression and increased PSA secretion by LNCaP cells. The effects of activin A and DHT to increase PSA production were synergistic or additive. Follistatin or bicalutamide was without effect on cell growth or PSA production. The effects of activin A on LNCaP cells were blocked by follistatin, not by bicalutamide, whereas effects of DHT were prevented by bicalutamide, not by follistatin. Activin A upregulates PSA production, and the effect is through an androgen receptor-independent pathway. The activin/follistatin system can be a physiological modulator of PSA gene transcription and secretion in the prostate tissue, and activins may cooperate with androgen to upregulate PSA in vivo.

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CR6-Interacting Factor 1 Represses the Transactivation of Androgen Receptor by Direct Interaction

Molecular Endocrinology ◽

10.1210/me.2007-0194 ◽

2008 ◽

Vol 22 (1) ◽

pp. 33-46 ◽

Cited By ~ 19

Author(s):

Ji Ho Suh ◽

Minho Shong ◽

Hueng-Sik Choi ◽

Keesook Lee

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Prostate Specific Antigen ◽

Transcriptional Activation ◽

Mrna Level ◽

Specific Antigen ◽

Negative Regulator ◽

Dependent Manner ◽

Target Promoters

Abstract CR6-interacting factor 1 (CRIF1) was previously identified as a nuclear protein that interacts with members of the Gadd45 family and plays a role as a negative regulator in cell growth. However, the nuclear function of CRIF1 remains largely unknown. In this study, we demonstrate that CRIF1 acts as a novel corepressor of the androgen receptor (AR) in prostatic cells. Transient transfection studies show that CRIF1 specifically represses AR transcriptional activation of target promoters in a dose-dependent manner. Additionally, CRIF1 is recruited with AR to the endogenous AR target promoters. In vivo and in vitro protein interaction assays reveal that CRIF1 directly interacts with AR via the activation function-1 domain of AR. Interestingly, both the N-terminal and C-terminal half-regions of CRIF1 are independently capable of interacting with and repressing the transactivation of AR. CRIF1 represses AR transactivation through competition with AR coactivators. In addition, the CRIF1-mediated inhibition of AR transactivation involves the recruitment of histone deacetylase 4. Down-regulation of CRIF1 by small interfering RNA increases the transactivation of AR and the mRNA level of the AR target gene prostate-specific antigen, whereas the overexpression of CRIF1 decreases the prostate-specific antigen mRNA level. Finally, the overexpression of CRIF1 inhibits the androgen-induced proliferation and cell cycle progression of prostate cancer cells. Taken together, these results suggest that CRIF1 acts as an AR corepressor and may play an important role in the regulation of AR-positive growth of prostate cancer.

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White button mushroom interrupts tissue AR-mediated TMPRSS2 expression and attenuates pro-inflammatory cytokines in C57BL/6 mice

npj Science of Food ◽

10.1038/s41538-021-00102-6 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Xiaoqiang Wang ◽

Desiree Ha ◽

Ryohei Yoshitake ◽

Shiuan Chen

Keyword(s):

Prostate Cancer ◽

Inflammatory Cytokines ◽

Suppressor Cells ◽

Edible Mushroom ◽

The United States ◽

Scientific Basis ◽

Asia Pacific ◽

Button Mushroom ◽

White Button Mushroom ◽

Pro Inflammatory Cytokines

AbstractWhite button mushroom (WBM) is a common edible mushroom consumed in the United States and many European and Asia-Pacific countries. We previously reported that dietary WBM antagonized dihydrotestosterone (DHT)-induced androgen receptor (AR) activation and reduced myeloid-derived suppressor cells (MDSCs) in prostate cancer animal models and patients. Transmembrane protease serine 2 (TMPRSS2), an androgen-induced protease in prostate cancer, has been implicated in influenza and coronavirus entry into the host cell, triggering host immune response. The present study on C57BL/6 mice revealed that WBM is a unique functional food that (A) interrupts AR-mediated TMPRSS2 expression in prostate, lungs, small intestine, and kidneys through its AR antagonistic activity and (B) attenuates serum pro-inflammatory cytokines and reduces MDSC counts through its immunoregulatory activity. These findings provide a scientific basis for translational studies toward clinical applications of WBM in diseases related to TMPRSS2 expression and immune dysregulation.

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A phase I, dose-expansion cohort study on the safety of a cannabidiol for biochemical recurrence in prostate cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps263 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS263-TPS263

Author(s):

Zin Myint ◽

William H. St Clair ◽

Stephen Strup ◽

Peng Wang ◽

Andrew Callaway James ◽

...

Keyword(s):

Prostate Cancer ◽

Acute Toxicity ◽

Phase I ◽

Cancer Patients ◽

Prostate Specific Antigen ◽

Dose Escalation ◽

Specific Antigen ◽

Dependent Manner ◽

Expansion Cohort

TPS263 Background: Cannabinoids, widely used in pain control, as an appetite stimulant, and anti-emetic in cancer patients, may play role as an anti-carcinogenic agent. A preclinical study demonstrated that cannabinoid receptors (CB1 and CB2) were highly expressed in human androgen-responsive prostate cancer (PCa) cells (LNCaP) as compared to normal prostate epithelial cells (PrEC). When these two cell lines were treated with a potent cannabinoid receptor agonist, PCa cells showed a decrease in prostate-specific antigen (PSA) protein expression and increased apoptosis in a dose and time-dependent manner with no effect seen in PrEC cells. An FDA-approved cannabidiol (CBD) agent, is derived from Cannabis sativa L. plants. Extracts from these plants are processed to yield pure CBD and contain less than 0.5% THC. We will expand these preclinical studies with a phase I trial. Methods: This trial is an open-label, single-center, phase I dose escalation study followed by dose expansion to evaluate acute toxicity, long-term safety and tolerability, and preliminary antitumor activity of cannabidiols in patients with biochemically recurrent (BCR) PC after primary definitive local therapy and prostate-specific antigen doubling time ≤ 12 months. The dose escalation will be determined by a Bayesian Optimal Interval design and the target dose-limiting toxicity rate is set at 30%. An additional 6-9 patients will be enrolled as an expansion cohort once the maximum tolerated dose is determined. Patients will be treated for a total 90 days with a 10 day taper. The primary objective is to evaluate the acute toxicity and long-term safety and tolerability of cannabidiols in patients with BCR. The secondary objective includes measuring changes in serial PSA levels, PSA velocity, and testosterone levels and to assess health-related quality of life (EORTC QLQ-C30 and QLQ-PR 25) from baseline throughout the treatment period. CB receptor 1 and 2 expression levels by immunohistochemistry staining will be evaluated from archival prostatectomy specimens if available as an exploratory objective. This trial opened on 7.28.2020 and has started enrollment. Clinical trial information: NCT04428203.

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