title: The role of NFATc1 in prostate cancer progression: cyclosporine A and tacrolimus inhibit cell proliferation, migration, and invasion.
abstract: BACKGROUND
  The functional role of nuclear factor of activated T-cells (NFAT), a well-characterized 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.
  
  
  METHODS
  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-small 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.
  
  
  RESULTS
  Immunohistochemistry revealed that the expression levels of NFATc1 were significantly elevated in prostatic carcinomas, compared with non-neoplastic prostate or high-grade prostatic intraepithelial neoplasia tissues, and in high-grade (Gleason scores ≥7) 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-myc, 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)-negative, AR-positive/androgen-sensitive, and AR-positive/castration-resistant lines. No significant additional inhibition in the growth of NFAT-siRNA cells by CsA and FK506 was seen, whereas these agents, especially FK506, further inhibited their invasion. In xenograft-bearing mice, CsA and FK506 significantly retarded tumor growth.
  
  
  CONCLUSIONS
  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-naïve but also castration-resistant prostate cancers.
authors: 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: Takashi
authors: T
authors: Kawahara
authors: Eiji
authors: E
authors: Kashiwagi
authors: Hiroki
authors: H
authors: Ide
authors: Yi
authors: Y
authors: Li
authors: Yichun
authors: Y
authors: Zheng
authors: Hitoshi
authors: H
authors: Ishiguro
authors: Hiroshi
authors: H
authors: Miyamoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D016559:Tacrolimus / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D016572:Cyclosporine; D016559:Tacrolimus
keywords: immunosuppressants; nuclear factor of activated T-cells; prostate cancer