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      Genistein treatment duration effects biomarkers of cell motility in human prostate

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          Abstract

          Background

          Long term dietary consumption of genistein by Chinese men is associated with decreased PCa metastasis and mortality. Short term treatment of US men with prostate cancer (PCa) with genistein decreases MMP-2 in prostate tissue. MEK4 regulates MMP-2 expression, drives PCa metastasis, and genistein inhibits MEK4, decreases MMP-2 expression and dietary dosing inhibits human PCa metastasis in mice. This study examines short- versus long-term treatment effects of genistein in humans and in vitro.

          Methods and findings

          US men with localized PCa were treated on a phase II trial with genistein (N = 14) versus not (N = 14) for one month prior to radical prostatectomy. Prostate epithelial cells were removed from fresh frozen tissue by laser capture microdissection, and the expression of 12,000 genes profiled. Genistein significantly altered the expression of four genes, three had established links to cancer cell motility and metastasis. Of these three, one was a non-coding transcript, and the other two were BASP1 and HCF2. Genistein increased BASP1 expression in humans, and its engineered over expression and knockdown demonstrated that it suppressed cell invasion in all six human prostate cell lines examined. Genistein decreased HCF2 expression in humans, and it was shown to increase cell invasion in all cell lines examined. The expression of MMP-2, MEK4 and BASP1 was then measured in formalin fixed prostate tissue from N = 38 Chinese men living in China and N = 41 US men living in the US, both cohorts with localized PCa. MMP-2 was 52% higher in Chinese compared to US tissue (P < 0.0001), MEK4 was 48% lower (P < 0.0001), and BASP1 was unaltered. Treatment of PC3 human PCa cells in vitro for up to 8 weeks demonstrated that short term genistein treatment decreased MMP-2, while long term treatment increased it, both changes being significant (P<0.05) compared to untreated control cells. Long term genistein-treated cells retained their responsiveness to genistein’s anti-motility effect.

          Conclusions

          Genistein inhibits pathways in human prostate that drive transformation to a lethal high motility phenotype. Long term treatment induces compensatory changes in biomarkers of efficacy. The current strategy of using such biomarkers after short term intervention as go/no-go determinants in early phase chemoprevention trials should be carefully examined.

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          Most cited references27

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          Expression profiling reveals hepsin overexpression in prostate cancer.

          Prostate cancer is the most commonly diagnosed noncutaneous cancer in men. Despite this fact, many of the genetic changes that coincide with prostate cancer progression remain enigmatic. We have addressed this problem by characterizing the expression profiles of several benign and malignant human prostate samples, and we have identified several genes that are differentially expressed between benign and malignant glands. One gene that was overexpressed encodes the serine protease hepsin. We used an independent sample set to confirm that hepsin is overexpressed in prostate tumors, and in situ hybridization demonstrates that hepsin is specifically overexpressed in the carcinoma cells themselves. These facts, together with the molecular properties of hepsin, make it an ideal target for prostate cancer therapy.
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            MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer.

            Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor beta (TGFbeta)-mediated increases in cell invasion are dependent upon activation of the serine/threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGFbeta treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wild-type MAPKAPK2 and HSP27 both increased TGFbeta-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGFbeta-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGFbeta-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGFbeta-mediated increases in MMP-2 and cell invasion in human prostate cancer.
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              Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Prostate Cancer Progression

              Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases involved in the degradation of the extracellular matrix, play an important role in tissue remodeling associated with various physiological processes such as morphogenesis, angiogenesis, and tissue repair, as well as pathological processes including cirrhosis, arthritis and cancer. The MMPs are well established as mediators of tumor invasion and metastasis by breaking down connective tissue barriers. Although there has been a vast amount of literature on the role of MMPs in invasion, metastasis and angiogenesis of various cancers, the role of these endopeptidases in prostate cancer progression has not been systematically reviewed. This overview summarizes findings on the tissue and blood expression of MMPs, their function, regulation and prognostic implication in human prostate cancer, with a focus on MMP-2, -7, -9, MT1-MMP and tissue inhibitor of metalloproteinase 1 (TIMP-1). This review also summarizes the efficacy and failure of early-generation matrix metalloproteinase inhibitors (MMPIs) in the treatment of metastatic prostate cancer and highlights the lessons and challenges for next generation MMPIs.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Validation
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administration
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Resources
                Role: Data curationRole: Resources
                Role: Data curationRole: Investigation
                Role: ConceptualizationRole: InvestigationRole: Methodology
                Role: Investigation
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 March 2019
                2019
                : 14
                : 3
                : e0214078
                Affiliations
                [1 ] Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
                [2 ] Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
                [3 ] Department of Pathology, Northwestern University, Chicago, Illinois, United States of America
                [4 ] Department of Urology, Northwestern University, Chicago, Illinois, United States of America
                [5 ] Department of Medicine, Northwestern University, Chicago, Illinois, United States of America
                [6 ] Department of Gastroenterology, Xiang’an Hospital of Xiamen University, FujianXiamen, China
                [7 ] Department of Preventive Medicine, Northwestern University, Chicago, Illinois, United States of America
                [8 ] Fred & Pamela Buffet Cancer Center, University Nebraska Medical Center, Omaha, Nebraska, United States of America
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: This does not alter our adherence to PLOS ONE policies on sharing data and materials. Patents awarded: 1. Catalytic Enantioselective Synthesis of Flavanones and Chromanones (US Patent # 7,851,640). Role: inventor. 2. Inhibition and Treatment of Prostate Cancer Metastasis (US Patent #s: 8,481,760, 8,742,141). Role: inventor. 3. Inhibition of Cancer Cell Motility (U.S. Patent #: 9,839,625). Role: inventor. Description: Work in point #1 describes the synthesis of new compounds that have the potential to inhibit cancer cell motility. Work in points 2 and 3 describes a different class of new compounds that do inhibit cancer cell motility and metastasis, and also identify a novel biological target for inhibiting those processes. That novel biological target involves selective modulation of HSP90 activity. Patents pending: Cell free screen for measuring effect of small molecules on client protein interactions with the HSP90B/CDC37 complex and resultant functional effects (US Patent Pending: U.S. Serial No. 62/628,243 -- VA ID No. 2017-383; A&A Ref. 30452.43USP1) Description: work in this pending application describes an in vitro method for screening of compounds that are selective HSP90 modulator Division of Hematology & Medical Oncology www.ohsu.edu/cancer. Cover Letter Page 2 of 2, Ownership interests: Raymond Bergan has the following relationships with Third Coast Therapeutics (3CRx) Inc.: cofounder, co-owner, member board of directors, Chief Scientific Officer. The focus of 3CRx is to move therapeutics licensed under above patents into human clinical trials to assess whether they will inhibit cancer cell motility and metastasis.

                Author information
                http://orcid.org/0000-0001-5822-6430
                http://orcid.org/0000-0001-8690-4876
                Article
                PONE-D-18-28484
                10.1371/journal.pone.0214078
                6436751
                30917169
                96d20e7d-4fe4-4024-be64-587c7b9f884d

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 7 October 2018
                : 6 March 2019
                Page count
                Figures: 4, Tables: 2, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;
                Award ID: IBX002842A
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA122985
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA90386
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality;
                Award ID: 16140903600
                Award Recipient :
                This study was supported with funding to R.B. by the U.S. Department of Veterans Affairs (IBX002842A) and the National Institutes of Health (R01 CA122985, Prostate SPORE CA90386 and P30 CA069533), and to H.J. from grant (16140903600) from Science and Technology Commission Shanghai Municipality. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Medicine and Health Sciences
                Urology
                Prostate Diseases
                Prostate Cancer
                Biology and Life Sciences
                Genetics
                Gene Expression
                Medicine and Health Sciences
                Oncology
                Metastasis
                Medicine and Health Sciences
                Oncology
                Basic Cancer Research
                Metastasis
                Biology and Life Sciences
                Cell Biology
                Cell Motility
                People and Places
                Population Groupings
                Ethnicities
                Chinese People
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Custom metadata
                All gene array related files are available from the NCBI GEO database (GSE128339). All other relevant data are within the manuscript and its Supporting Information files.

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                Uncategorized

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