Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine

Many different types of cancer cells have been shown to be methionine‐dependent. These cells, unlike normal cells, grow poorly or not at all when methionine is replaced by its immediate precursor homocysteine in the growth medium (Met−Hcy+ medium). We have previously shown that apparently normal total amounts of methionine are synthesized by methionine‐dependent SV40‐transformed human fibroblasts. However, methionine‐dependent cells in Met−Hcy+ medium accumulate reduced amounts of S‐adenosylmethionine (AdoMet) and elevated amounts of S‐adenosylhomo‐cysteine (AdoHcy) that together probably limit growth. In this report, we demonstrate that the amount of free methionine is low in methionine‐dependent SV40‐transformed human fibroblasts in Met−Hcy+ medium compared to normal human diploid fibroblasts. In contrast, in Met+Hcy− medium, the amount of free methionine is comparable in both cell types. The deficient pool of free methionine in methionine‐dependent cells in Met−Hcy+ medium allows only low amounts of AdoMet to be formed. However, large amounts of the biosynthesized methionine are channeled into protein synthesis. Possible mechanisms are discussed to explain this cancer‐associated metabolic defect.