NFAT3 is specifically required for TNF-alpha-induced cyclooxygenase-2 (COX-2) expression and transformation of Cl41 cells.
NFAT family is recognized as a transcription factor for inflammation regulation by inducing the expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), the key mediator of inflammation, which was reported to induce cell transformation in mouse epidermal Cl41 cells. In this study, we demonstrated that TNF-alpha was able to induce NFAT activation, as well as the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). The induction of COX-2 by TNF-alpha was abolished by knockdown of NFAT3 with its siRNA, while the induction of iNOS was not effected. Moreover, TNF-alpha-induced anchorage-independent cell growth was significantly inhibited by NFAT3 siRNA and cyclosporine A, a chemical inhibitor for the calcineurin/NFAT pathway, which suggests the importance of NFAT3 in regulating TNF-alpha-induced anchorage-independent cell growth. Consequently, impairment of COX-2 by its siRNA or selective inhibitor also inhibited TNF-alpha-induced anchorage-independent cell growth. Taken together, our results indicate that NFAT3 plays an important role in the regulation of TNF-alpha-induced anchorage-independent cell growth, at least partially, by inducing COX-2 expression in Cl41 cells. These findings suggest that NFAT3/cyclooxygenase-2 act as a link between inflammation and carcinogenesis by being involved in the tumor promotion stage.
Yan
Yan
Y
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Li
Jingxia
J
Ouyang
Weiming
W
Ma
Qian
Q
Hu
Yu
Y
Zhang
Dongyun
D
Ding
Jin
J
Qu
Qingshan
Q
Subbaramaiah
Kotha
K
Huang
Chuanshu
C
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D050778:NFATC Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2