Modulation of tumor necrosis factor-alpha-mediated cytotoxicity by changes of the cellular methylation state: mechanism and in vivo relevance.
A combination of adenosine (Ado) and homocysteine (Homo) enhances tumor necrosis factor (TNF)-alpha cytotoxicity in vitro and in vivo in several tumor cells. Ado and Homo at concentrations that enhanced TNF-alpha-mediated cytotoxicity accumulated S-adenosylhomocysteine (AdoHcy) and as consequence decreased the cellular methylation state, i.e. the ratio of S-adenosylmethionine to AdoHcy. This decrease led to inhibition of the isoprenylcysteine carboxyl methyltransferase (MTase), an enzyme that catalyzes carboxyl methylation of C-terminal cysteine residues on isoprenylated proteins. The effect of Ado and Homo on TNF-alpha cytotoxicity was at least partly mimicked by S-farnesylthioacetic acid, a selective inhibitor of the isoprenylcysteine carboxyl MTase, suggesting involvement of methylations of prenylated proteins in TNF-alpha-mediated cytotoxicity. Blockage of methylation reactions was associated with an enhancement of the TNF-alpha-induced disruption of the mitochondrial membrane potential (delta psi(m)). In nude mice, a combination of Ado, Homo and TNF-alpha led to TNF-alpha-induced hemorrhagic necrosis and growth inhibition of TNF-sensitive L929 tumors, whereas little effect was observed with TNF-alpha alone. Even more important, the TNF-resistant L929 M1 tumors were rendered TNF-sensitive by the combined action of Ado and Homo. We conclude that Ado and Homo together enhance the effectiveness of TNF-alpha in vitro and in vivo, results that may have therapeutic implications.
D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D008564:Membrane Potentials; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000502:physiology; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*