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NFATc2 is a potential therapeutic target in human melanoma.
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.
Human Tumors Immunobiology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., , , , , , , ,
Cell Line, Tumor
Inhibitor of Apoptosis Proteins
MAP Kinase Signaling System
NFATC Transcription Factors
Proto-Oncogene Proteins B-raf
TNF-Related Apoptosis-Inducing Ligand
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't