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Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and
S Mazurek1, W Zwerschke, P Jansen-Dürr
1Institute for Biochemistry and Endocrinology, Veterinary Faculty, University of Giessen, Frankfurter Strasse 100, 35392 Giessen, Germany. Sybille.Mazurek@vetmed.uni-giessen.de
Oncogene
|November 1, 2001
Summary
Oncogenic ras upregulates fructose 1,6-bisphosphate (FBP) and pyruvate kinase M2 (M2-PK), driving tumor metabolism. The HPV-16 E7 oncoprotein then binds M2-PK, restoring cell proliferation.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Tumor cells exhibit a distinct metabolic profile (tumor metabolome) characterized by high glycolytic enzyme concentration, particularly pyruvate kinase isoenzyme type M2 (M2-PK), elevated glutaminolytic capacity, high fructose 1,6-bisphosphate (FBP) levels, and a reduced (ATP+GTP):(CTP+UTP) ratio.
- The precise sequence of metabolic events leading to the establishment of the tumor metabolome remains unclear.
Purpose of the Study:
- To elucidate the sequence of metabolic alterations contributing to the tumor metabolome.
- To investigate the roles of oncogenic ras and HPV-16 E7 oncoprotein in shaping cellular metabolism.
Main Methods:
- Stable expression of oncogenic ras in non-transformed rat kidney (NRK) cells.
- Analysis of metabolic parameters including fructose 1,6-bisphosphate (FBP) levels, pyruvate kinase isoenzyme type M2 (M2-PK) activity, and nucleotide ratios.
- Investigation of the interaction between HPV-16 E7 oncoprotein and M2-PK.
Main Results:
- NRK cells exhibited high glutaminolytic flux and a low (ATP+GTP):(CTP+UTP) ratio, but low FBP levels and M2-PK activity.
- Ras expression led to increased FBP levels and M2-PK activity, causing M2-PK tetramerization and migration into glycolytic enzyme complexes, increased AMP, and decreased UTP/CTP levels.
- Ras expression initiated the glycolytic shift, inhibiting nucleic acid synthesis and proliferation.
- HPV-16 E7 oncoprotein directly bound to M2-PK, induced dimerization, and restored nucleic acid synthesis and proliferation.
Conclusions:
- Ras-induced metabolic changes initiate the glycolytic reprogramming characteristic of tumor cells.
- The combined actions of ras and HPV-16 E7 oncoprotein establish the complete tumor metabolome by modulating M2-PK activity and nucleotide pools.
- This study reveals a key mechanism by which viral oncoproteins cooperate with cellular oncogenes to drive cancer metabolism and proliferation.