International Immunology, Vol. 11, No. 4, 519-527,
April 1999
© 1999 Japanese Society for Immunology
Modulation of tumor necrosis factor-
-mediated cytotoxicity by changes of the cellular methylation state: mechanism and in vivo relevance
German Cancer Research Center, Division of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Correspondence to: V. Lehmann
A combination of adenosine (Ado) and homocysteine (Homo) enhances tumor necrosis factor (TNF)-
cytotoxicity in vitro and in vivo in several tumor cells. Ado and Homo at concentrations that enhanced TNF--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- 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--mediated cytotoxicity. Blockage of methylation reactions was associated with an enhancement of the TNF--induced disruption of the mitochondrial membrane potential (
m). In nude mice, a combination of Ado, Homo and TNF- led to TNF--induced hemorrhagic necrosis and growth inhibition of TNF-sensitive L929 tumors, whereas little effect was observed with TNF- 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- in vitro and in vivo, results that may have therapeutic implications.
Keywords: cancer therapy, carboxyl methyltransferase, depolarization, tumor growth
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