title: Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway.
abstract: Chronic inflammation is a risk factor for the development of colon cancer, providing genotoxic insults, growth and pro-angiogenic factors that can promote tumorigenesis and tumor growth. Immunomodulatory agents can interfere with the inflammation that feeds cancer, but their impact on the transformed cell is poorly understood. The calcium/calcineurin signaling pathway, through activation of NFAT, is essential for effective immune responses, and its inhibitors cyclosporin A (CsA) and FK506 are used in the clinics to suppress immunity. Moreover, the kinases GSK3β and mTOR, modulated by PI-3K/Akt, can inhibit NFAT activity, suggesting a cross-talk between the calcium and growth factor signaling pathways. Both NFAT and mTOR activity have been associated with tumorigenesis. We therefore investigated the impact of calcineurin and PI-3K/mTOR inhibition in growth of human colon carcinoma cells. We show that despite the efficient inhibition of NFAT1 activity, FK506 promotes tumor growth, whereas CsA inhibits it due to a delay in cell cycle progression and induction of necroptosis. We found NFκB activation and mTORC1 activity not to be altered by CsA or FK506. Similarly, changes to mitochondrial homeostasis were equivalent upon treatment with these drugs. We further show that, in our model, NFAT1 activation is not modulated by PI3K/mTOR. We conclude that CsA slows cell cycle progression and induces necroptosis of human carcinoma cell lines in a TGFβ-, NFAT-, NFκB- and PI3K/mTOR-independent fashion. Nevertheless, our data suggest that CsA, in addition to its anti-inflammatory capacity, may target transformed colon and esophagus carcinoma cells without affecting non-transformed cells, promoting beneficial tumoristatic effects.
authors.affiliation: Division of Cellular Biology, Brazilian National Institute of Cancer (INCA), Rio de Janeiro, RJ Brazil.
authors.forename: Miriam B F
authors.initials: MB
authors.lastname: Werneck
authors.forename: Eugênio
authors.initials: E
authors.lastname: Hottz
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: João P B
authors.initials: JP
authors.lastname: Viola
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D019703:Calcineurin; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; C546842:MTOR protein, human