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Methionine-sensitive glycolysis in transformed cells
Abstract:
Glycolysis in several tumor cell lines grown in tissue culture was inhibited by methionine. Kirsten murine sarcoma virus-transformed rat kidney cells (K-NRK) were inhibited 60-75% by 10 mM methionine, whereas normal rat kidney (NRK-49F) cells showed little or no inhibition. Inhibition of glycolysis in K-NRK cells was manifest 2-4 hr after exposure to the amino acid. Glycolysis in a chemically transformed cell line of Madin-Darby canine kidney cells was also sensitive to methionine, but maximal inhibition (75%) required 18-24 hr of incubation with the amino acid. Under the same conditions glycolysis in the nontransformed canine cells was less than 20% inhibited by methionine. In Ehrlich ascites tumor cells grown in tissue culture, 10 mM methionine inhibited glycolysis by about 50%. Inhibition of glycolysis, even by 50 mM methionine, was rapidly reversible. Within 2 hr after removal of methionine the rate of glycolytic activity was restored to that observed in control cells. Furthermore, inhibition by methionine required a minimum level (7%) of serum in the growth medium and inhibition was not sensitive to cycloheximide. Only amino acids that are transported by system A (including the nonmetabolized analogue methylaminoisobutyric acid) specifically inhibited glycolysis in tumor cells. The only exception was phenylalanine, which was toxic to both transformed and normal cell lines.
Insights
Methionine selectively inhibits glycolysis in tumor cells, not normal cells. This effect is reversible and linked to specific amino acid transporters, offering potential therapeutic insights.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Tumor cells exhibit altered metabolic pathways, including enhanced glycolysis (the Warburg effect).
- Targeting tumor cell metabolism is a promising strategy for cancer therapy.
Purpose of the Study:
- To investigate the effect of methionine on glycolysis in various tumor and normal cell lines.
- To understand the specificity and reversibility of methionine-induced glycolytic inhibition.
Main Methods:
- Culturing of Kirsten murine sarcoma virus-transformed rat kidney (K-NRK) cells, normal rat kidney (NRK-49F) cells, chemically transformed canine kidney cells, normal canine kidney cells, and Ehrlich ascites tumor cells.
- Treatment with varying concentrations of methionine and measurement of glycolysis rates.
- Assessment of reversibility by removing methionine and evaluating glycolytic activity.
- Testing the role of serum concentration and cycloheximide.
- Investigating the specificity of amino acid transport systems.
Main Results:
- Methionine significantly inhibited glycolysis in K-NRK cells (60-75%) and Ehrlich ascites tumor cells (approx. 50%) but had minimal effect on normal rat kidney cells.
- Chemically transformed canine cells showed sensitivity to methionine, unlike their normal counterparts.
- Inhibition was reversible within 2 hours of methionine removal.
- Methionine's inhibitory effect required a minimum serum level (7%) and was not affected by cycloheximide.
- Amino acids transported by system A specifically inhibited tumor cell glycolysis, with phenylalanine being an exception.
Conclusions:
- Methionine selectively inhibits glycolysis in transformed and tumor cells.
- The inhibition is dependent on specific amino acid transporters (System A) and is rapidly reversible.
- These findings suggest a potential metabolic vulnerability in tumor cells that can be targeted by specific amino acids.