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NFATc2 is a potential therapeutic target in human melanoma.

Abstract

The identification of intracellular signaling pathways that promote cell proliferation and resistance to cell death may lead to the development of improved treatment for advanced melanoma. Here we show that the calcineurin/nuclear factor of activated T cells c2 (NFATc2) pathway has an antiapoptotic role in melanoma cells. Expression of NFATc2 was constitutive in vitro and in vivo in human melanoma, and cyclosporin A (CsA) treatment of melanoma cells led to downmodulation of NFATc2. Inhibition of the calcineurin/NFAT pathway by CsA, or by NFATc2 silencing, led to modulation of cell cycle inhibitors and apoptosis-related proteins such as Apollon, and promoted caspase-dependent apoptosis of neoplastic cells. Calcineurin/NFATc2 targeting significantly enhanced melanoma cell death induced by antitumor agents, such as MEK- or BRAF(V600E)-specific inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand, which trigger the intrinsic or extrinsic pathway of apoptosis, respectively. These findings identify NFATc2 as a potential therapeutic target in melanoma.

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  • Authors

    Perotti V, Baldassari P, Bersani I, Molla A, Vegetti C, Tassi E, Dal Col J, Dolcetti R, Anichini A, Mortarini R

    Source

    The Journal of investigative dermatology 132:11 2012 Nov pg 2652-60

    MeSH

    Apoptosis
    Calcineurin
    Caspase 2
    Caspase 3
    Cell Line, Tumor
    Cell Proliferation
    Cyclosporine
    Cysteine Endopeptidases
    Down-Regulation
    Enzyme Inhibitors
    Humans
    Inhibitor of Apoptosis Proteins
    MAP Kinase Signaling System
    Melanoma
    NFATC Transcription Factors
    Proto-Oncogene Proteins B-raf
    Skin Neoplasms
    TNF-Related Apoptosis-Inducing Ligand

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22718120