Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth

Molecular Cancer

Research

Hanan Farghaly¹  Alden C Klarer²  Kristin K Nelson²  Abdullah Yalcin²  Deanna L Siow²  Joshua M Thornburg²  Brian F Clem²  Jason Chesney²  Yoannis Imbert-Fernandez²  John W Eaton²  Sucheta Telang² 

[1]Department of Pathology, University of Louisville, Louisville, KY, USA

[2]Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

关键词: Mitochondria;    Glycolysis;    Tricarboxylic acid cycle;    Electron transport chain;    Oncogene;   

DOI  :  10.1186/1476-4598-11-60

 received in 2012-05-25, accepted in 2012-08-17,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundConstitutive activation of Ras in immortalized bronchial epithelial cells increases electron transport chain activity, oxygen consumption and tricarboxylic acid cycling through unknown mechanisms. We hypothesized that members of the Ras family may stimulate respiration by enhancing the expression of the Vb regulatory subunit of cytochrome c oxidase (COX).ResultsWe found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells increased eIF4E-dependent COX Vb protein expression simultaneously with an increase in COX activity and oxygen consumption. In support of the regulation of COX Vb expression by the Ras family, we also found that selective siRNA-mediated inhibition of K-Ras expression in A549 lung adenocarcinoma cells reduced COX Vb protein expression, COX activity, oxygen consumption and the steady-state concentration of ATP. We postulated that COX Vb-mediated activation of COX activity may be required for the anchorage-independent growth of A549 cells as soft agar colonies or as lung xenografts. We transfected the A549 cells with COX Vb small interfering or shRNA and observed a significant reduction of their COX activity, oxygen consumption, ATP and ability to grow in soft agar and as poorly differentiated tumors in athymic mice.ConclusionTaken together, our findings indicate that the activation of Ras increases COX activity and mitochondrial respiration in part via up-regulation of COX Vb and that this regulatory subunit of COX may have utility as a Ras effector target for the development of anti-neoplastic agents.

【 授权许可】

Unknown   
© Telang et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.