Sub-apoptotic dosages of pro-oxidant vitamin cocktails sensitize human melanoma cells to NK cell lysis
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Elisa Tremante1, Lory Santarelli2, Elisa Lo Monaco1, Camilla Sampaoli1, Tiziano Ingegnere1, Roberto Guerrieri3, Marco Tomasetti2,*, Patrizio Giacomini1,*
1Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy
2Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020 Ancona, Italy
3Center of Excellence on Electronic Systems (ARCES), University of Bologna, 40123 Bologna, Italy
*These authors have contributed equally to this work
Patrizio Giacomini, e-mail: email@example.com
Keywords: melanoma, autoschizis, oxidative stress, NKG2D, Natural Cytotoxicity Receptors (NCR)
Received: April 23, 2015 Accepted: August 24, 2015 Published: September 05, 2015
Alpha-tocopheryl succinate (αTOS), vitamin K3 (VK3) and vitamin C (ascorbic acid, AA) were previously shown to synergistically promote different death pathways in carcinoma cells, depending on their concentrations and combinations. Similar effects were observed herein in melanoma cells, although αTOS behaved as an antagonist. Interestingly, suboptimal cell death-inducing concentrations (1.5 μM αTOS/20 μM AA/0.2 μM VK3) effectively up-regulated activating Natural Killer (NK) cell ligands, including MICA (the stress-signaling ligand of the NKG2D receptor), and/or the ligands of at least one of the natural cytotoxicity receptors (NKp30, NKp44 and NKp46) in 5/6 melanoma cell lines. Only an isolated MICA down-regulation was seen. HLA class I, HLA class II, ULBP1, ULBP2, ULBP3, Nectin-2, and PVR displayed little, if any, change in expression. Ligand up-regulation resulted in improved lysis by polyclonal NK cells armed with the corresponding activating receptors. These results provide the first evidence for concerted induction of cell death by cell-autonomous and extrinsic (immune) mechanisms. Alarming the immune system much below the cell damage threshold may have evolved as a sensitive readout of neoplastic transformation and oxidative stress. Cocktails of vitamin analogues at slightly supra-physiological dosages may find application as mild complements of melanoma treatment, and in chemoprevention.
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