Research

The oncoprotein H-Ras^V12 increases mitochondrial metabolism

Sucheta Telang¹ , Andrew N Lane² , Kristin K Nelson¹ , Sengodagounder Arumugam² and Jason Chesney¹

¹  Molecular Targets Group, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA

²  Structural Biology Program, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA

author email corresponding author email

Molecular Cancer 2007, 6:77doi:10.1186/1476-4598-6-77

Published:	1 December 2007

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-Ras^V12-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-Ras^V12 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-Ras^V12-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-Ras^V12 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-Ras^V12 increases mitochondrial metabolism and provide new rationale for the targeting of the tricarboxylic acid cycle and electron transport chain as anti-neoplastic strategies.