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.

Links

Publisher Full Text

Authors

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

Institution

Human Tumors Immunobiology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

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