title: Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1.
abstract: The functional role of nuclear factor of activated T-cells (NFAT), a key regulator of the immune response, in bladder cancer progression remains uncertain. In this study, we assessed biological significance of NFAT in human bladder cancer. Immunohistochemistry detected nuclear/cytoplasmic NFATc1 signals in 14 (21.5%)/34 (52.3%), respectively, of 65 muscle-invasive bladder carcinomas and showed that patients with nuclear NFATc1-positive tumor had a significantly higher risk of disease progression (P = 0.006). In bladder cancer cell lines, cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressant drugs/non-selective NFAT inhibitors, attenuated NFATc1 expression and its nuclear translocation, NFAT transcriptional activity, and the expression of cyclooxygenase-2 and c-myc, downstream targets of NFATc1. NFAT inhibition via NFATc1-small interfering RNA (siRNA) or treatment with these NFAT inhibitors resulted in decreases in cell viability/colony formation, cell migration/invasion, and the expression/activity of MMP-2 and MMP-9, as well as an increase in apoptosis, in the parental/control lines. No significant additional inhibition in the viability and invasion of NFATc1-siRNA cells was seen. In xenograft-bearing mice, CsA and FK506 significantly retarded tumor growth. These results suggest that NFATc1 plays an important role in bladder cancer outgrowth. Thus, NFATc1 inactivation, especially using CsA and FK506, has the potential of being a therapeutic approach for bladder cancer.
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Takashi
authors: T
authors: Kawahara
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Eiji
authors: E
authors: Kashiwagi
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Hiroki
authors: H
authors: Ide
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Yi
authors: Y
authors: Li
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Yichun
authors: Y
authors: Zheng
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Yurina
authors: Y
authors: Miyamoto
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: George J
authors: GJ
authors: Netto
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Hitoshi
authors: H
authors: Ishiguro
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Hiroshi
authors: H
authors: Miyamoto
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016559:Tacrolimus / Q000008:administration & dosage; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D016572:Cyclosporine; D016559:Tacrolimus
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