title: NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence.
abstract: Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1β, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.
authors.affiliation: Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Manda
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, MO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Hsi
authors.affiliation: Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA.|The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ning
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, MO, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Ruzinova
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, MO, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liapis
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA.|The Genome Institute, Washington University, St Louis, MO, USA.|Siteman Cancer Center, Washington University, St Louis, MO, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Maher
authors.affiliation: Department of Pathology, Yale University, New Haven, CT, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Humphrey
authors.affiliation: Siteman Cancer Center, Washington University, St Louis, MO, USA.|Department of Surgery, Washington University, St Louis, MO, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Andriole
authors.affiliation: Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA.|The Genome Institute, Washington University, St Louis, MO, USA.|Siteman Cancer Center, Washington University, St Louis, MO, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Structural and Cellular Biology, Tulane University, New Orleans, LA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: You
authors.affiliation: Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA.|Siteman Cancer Center, Washington University, St Louis, MO, USA.|Department of Cell Biology and Physiology, Washington University, St Louis, MO, USA.
authors.forename: F
authors.initials: F
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D016207:Cytokines; D050778:NFATC Transcription Factors; D051059:PTEN Phosphohydrolase