title: Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis.
abstract: The functional role of nuclear factor of activated T-cells (NFAT), while it has been extensively investigated in the immune system, remains uncertain in bladder cancer development. We here aim to assess the effects of cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressants known to specifically inactivate the NFAT pathway in immune cells, on neoplastic transformation of urothelial cells. Immunohistochemistry revealed that the expression levels of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, were elevated in urothelial neoplasms, compared with non-neoplastic urothelial tissues, and in low-grade and high-grade papillary urothelial carcinomas, compared with papillary urothelial neoplasms of low malignant potential. In an immortalized normal urothelial cell line SVHUC, CsA and FK506 reduced NFATc1 expression, NFAT transcriptional activity, and the expression of c-myc, a downstream target of NFATc1 signals. Treatment with CsA or FK506 in the SVHUC cells undergoing neoplastic transformation induced by exposure to a chemical carcinogen 3-methylcholanthrene resulted in strong inhibition in colony formation in vitro as well as tumor formation in NOD-SCID mice. CsA and FK506 were additionally found to up-regulate the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and p27, and down-regulate that of oncogenic genes, such as cyclin D1, cyclin D3, and cyclin E, in SVHUC cells with the carcinogen challenge. Thus, CsA and FK506 likely inhibit urothelial tumorigenesis. These findings offer a potential chemopreventive approach for urothelial tumors using NFAT inhibitors.
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawahara
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Yurina
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishiguro
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008748:Methylcholanthrene / Q000009:adverse effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D008748:Methylcholanthrene; D016572:Cyclosporine; D016559:Tacrolimus
keywords: NFAT; bladder cancer; carcinogenesis; inhibitors; neoplastic transformation