The oncoprotein H-RasV12 increases mitochondrial metabolism.
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.


CONCLUSIONS
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.
Telang
Sucheta
S
Molecular Targets Group, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA. sucheta.telang@louisville.edu
Lane
Andrew N
AN
Nelson
Kristin K
KK
Arumugam
Sengodagounder
S
Chesney
Jason
J
D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
D007773:Lactates; D016283:Proto-Oncogene Proteins p21(ras); D005947:Glucose