{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T21:25:08Z","timestamp":1789939508230,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,1,28]],"date-time":"2015-01-28T00:00:00Z","timestamp":1422403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The functional role of nuclear factor of activated T\u2010cells (NFAT), a well\u2010characterized regulator of the immune response, in prostate cancer progression remains largely unknown. We aim to investigate biological significance of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, in human prostate cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We first determined the expression levels of NFAT in prostate cell lines and tissue specimens. We then assessed the effects of NFAT inhibition via NFATc1\u2010small interfering RNA (siRNA) as well as immunosuppressants including cyclosporine A (CsA) and tacrolimus (FK506) on prostate cancer cell proliferation, apoptosis, migration, and invasion in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Immunohistochemistry revealed that the expression levels of NFATc1 were significantly elevated in prostatic carcinomas, compared with non\u2010neoplastic prostate or high\u2010grade prostatic intraepithelial neoplasia tissues, and in high\u2010grade (Gleason scores \u22657) tumors. NFATc1 positivity in carcinomas, as an independent prognosticator, also correlated with the risk of biochemical recurrence after radical prostatectomy. In prostate cancer cell lines, CsA and FK506 inhibited NFATc1 expression and its nuclear translocation, NFAT transcriptional activity, and the expression of c\u2010myc, a downstream target of NFAT. NFAT silencing or treatment with these NFAT inhibitors resulted in decreases in cell viability\/colony formation and cell migration\/invasion, as well as increases in apoptosis, in androgen receptor (AR)\u2010negative, AR\u2010positive\/androgen\u2010sensitive, and AR\u2010positive\/castration\u2010resistant lines. No significant additional inhibition in the growth of NFAT\u2010siRNA cells by CsA and FK506 was seen, whereas these agents, especially FK506, further inhibited their invasion. In xenograft\u2010bearing mice, CsA and FK506 significantly retarded tumor growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Our results suggest that NFATc1 plays an important role in prostate cancer outgrowth. Thus, NFATc1 inactivation, especially using CsA and FK506, has the potential of being a therapeutic approach for not only hormone\u2010na\u00efve but also castration\u2010resistant prostate cancers.<jats:italic>Prostate 75: 573\u2013584, 2015<\/jats:italic>. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.22937","type":"journal-article","created":{"date-parts":[[2015,1,28]],"date-time":"2015-01-28T17:15:35Z","timestamp":1422465335000},"page":"573-584","source":"Crossref","is-referenced-by-count":42,"title":["The role of NFATc1 in prostate cancer progression: Cyclosporine A and tacrolimus inhibit cell proliferation, migration, and invasion"],"prefix":"10.1002","volume":"75","author":[{"given":"Takashi","family":"Kawahara","sequence":"first","affiliation":[{"name":"Departments of Pathology and Urology Johns Hopkins University School of Medicine Baltimore Maryland"},{"name":"Department of Pathology and Laboratory Medicine University of Rochester Medical 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