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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Calcineurin / metabolism
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Caspase 2 / metabolism
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclosporine / pharmacology
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Cysteine Endopeptidases / metabolism
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Enzyme Inhibitors / pharmacology
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Melanoma / drug therapy
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Melanoma / metabolism*
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Melanoma / pathology
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NFATC Transcription Factors / metabolism*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Skin Neoplasms / drug therapy
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
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TNF-Related Apoptosis-Inducing Ligand / metabolism
Substances
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BIRC6 protein, human
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Enzyme Inhibitors
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Inhibitor of Apoptosis Proteins
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NFATC Transcription Factors
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NFATC1 protein, human
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NFATC2 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Cyclosporine
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Calcineurin
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CASP2 protein, human
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CASP3 protein, human
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Caspase 2
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Caspase 3
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Cysteine Endopeptidases