Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and...

The metabolism of tumor cells (tumor metabolome) is characterized by a high concentration of glycolytic enzymes including pyruvate kinase isoenzyme type M2 (M2-PK), a high glutaminolytic capacity, high fructose 1,6-bisphosphate (FBP) levels and a low (ATP+GTP):(CTP+UTP) ratio. The sequence of events required for the establishment of the tumor metabolome is presently unknown. In non-transformed rat kidney (NRK) cells we observed a high glutaminolytic flux rate and a low (ATP+GTP):(CTP+UTP) ratio, whereas FBP levels and M2-PK activity are still extremely low. After stable expression of oncogenic ras in NRK cells a strong upregulation of FBP levels and of M2-PK activity was observed. Elevated FBP levels induce a tetramerization of M2-PK and its migration into the glycolytic enzyme complex. AMP levels increase whereas UTP and CTP levels strongly decrease. Thus, ras expression completes the glycolytic part of tumor metabolism leading to the inhibition of nucleic acid synthesis and cell proliferation. The HPV-16 E7 oncoprotein, which cooperates with ras in cell transformation, directly binds to M2-PK, induces its dimerization and restores nucleic acid synthesis as well as cell proliferation. Apparently, the combination of the different metabolic effects of ras and E7 constructs the perfect tumor metabolome as generally found in tumor cells.