Patterns of Methionine Auxotrophy in Normal and Neoplastic Cells: The Methionine Independence of Lymphocyte Mitogenesis and Low Frequency of the Methionine-dependent Phenotype in Human Tumors

Abstract

Seven murine and 17 human tumor-derived cell lines were tested for their ability to grow in methionine-free medium containing the methionine precursor homocysteine. Three murine tumors, SP1, MDAY-D2, and L1210, failed to grow in this medium and were therefore methionine dependent (Met-Dep). In contrast, all human tumors, including 8 recently established cell lines, were methionine independent (Met-Indep). Concanavalin A-induced lymphocyte mitogenesis was also Met-Indep but required 3 to 4 times the amount of homocysteine needed for the growth of normal fibroblasts or Met-Indep tumors. In addition, lymphocyte mitogenesis was also supported by exogenous 5′-methylthioadenosine, another methionine precursor formed during polyamine synthesis. In contrast, Met-Dep tumors did not respond to increasing homocysteine concentration, nor was their growth supported by 5′-methylthioadenosine.

These findings demonstrate that Met-Dep can occur by varied mechanisms relating to such parameters as homocysteine concentration and the ability of cells to generate Met-Indep revertants or to grow in 5′-methylthioadenosine. In general, we found the Met-Dep phenotype to be more common in murine tumor cells and to occur infrequently in human tumors. This may imply a species difference in methionine metabolism.