title: Inhibition of androgen receptor and β-catenin activity in prostate cancer.
abstract: Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin-signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, Stem Cell Biology, Microbiology, Urology, and New York University Cancer Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Eugine
authors.initials: E
authors.lastname: Lee
authors.forename: Aviv
authors.initials: A
authors.lastname: Madar
authors.forename: Gregory
authors.initials: G
authors.lastname: David
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Dasgupta
authors.forename: Susan K
authors.initials: SK
authors.lastname: Logan
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D051176:beta Catenin
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