The oncoprotein H-RasV12 increases mitochondrial metabolism

Mol Cancer. 2007 Dec 1;6:77. doi: 10.1186/1476-4598-6-77.

Abstract

Background: Neoplastic cells increase glycolysis in order to produce anabolic precursors and energy within the hypoxic environment of a tumor. Ras signaling is activated in several cancers and has been found to regulate metabolism by enhancing glycolytic flux to lactate. We examined the effects of sequential immortalization and H-RasV12-transformation of human bronchial epithelial cells on the anabolic fate of fully-labeled 13C-glucose-derived carbons using two-dimensional total correlated spectroscopic analysis-nuclear magnetic resonance spectroscopy (2D TOCSY-NMR).

Results: We found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells unexpectedly increased tricarboxylic acid cycle activity as measured by the direct conversion of 13C-glucose carbons into the anabolic substrates glutamate/glutamine, aspartate and uridine. We then observed that immortalization and H-RasV12-transformation of bronchial epithelial cells caused a stepwise increase in oxygen consumption, a global measure of electron transport chain activity. Importantly, ectopic expression of H-RasV12 sensitized immortalized cells to the ATP-depleting and cytotoxic effects of electron transport perturbation using the complex I inhibitor rotenone.

Conclusion: Taken together, these data indicate that the oncoprotein H-RasV12 increases mitochondrial metabolism and provide new rationale for the targeting of the tricarboxylic acid cycle and electron transport chain as anti-neoplastic strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bronchi / cytology
  • Bronchi / metabolism
  • Cell Line, Transformed
  • Epithelial Cells / metabolism
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Lactates / metabolism
  • Mitochondria / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Proto-Oncogene Proteins p21(ras) / physiology*

Substances

  • Lactates
  • Proto-Oncogene Proteins p21(ras)
  • Glucose