Defects in Methylthioadenosine Phosphorylase Are Associated with but Not Responsible for Methionine-dependent Tumor Cell Growth

A large proportion of human tumor-derived cell lines and primary tumor cells show methionine-dependent growth. This phenomenon refers to the ability of cells to grow in media containing methionine and the inability of cells to grow in media supplemented with methionine's precursor, homocysteine (Hcy). Methionine can be formed by two different pathways, the recycling pathway and the salvage pathway. To discover the basis for methionine-dependent growth, we have analyzed 12 tumor cell lines and 2 non-tumor-derived cell lines for defects in two key genes in different methionine synthetic pathways. We found little evidence that defects in methionine synthase expression or mutations in the MS gene are correlated with methionine-dependent growth. However, we did find a correlation between methionine-dependent growth and defects in expression of methylthioadenosine phosphorylase (MTAP), a key enzyme in the salvage pathway. Three of the four cell lines lacking detectable MTAP protein were unable to grow in Hcy-containing media, whereas all six of the MTAP-positive cell lines tested showed strong growth. However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting cell line was still defective in growth on Hcy, although it could now grow on the salvage pathway precursor methylthioadenosine. These findings indicate that salvage pathway defects are not causally related to methionine-dependent growth.