Etiology and Pathogenesis > Tumor Biology

Cancer Cell, Vol 9, 425-434, 13 June 2006. DOI 10.1016/j.ccr.2006.04.023. Available online 12 June 2006

Abstract
Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance

Valeria R. Fantin1, 3, 4, Julie St-Pierre2, 3, 5 and Philip Leder1,*

1Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115. 2Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115. 3 These authors contributed equally to this work. 4 Present address: Merck & Co., Inc., Boston, Massachusetts 02115. 5 Present address: Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal Pavillon Marcelle-Coutu, Montréal, Québec, Canada H3T 1J4.
*Corresponding Author. Ph: 617 992 2097; Fax: 617 992 2412.
Received 21 November 2005;  revised 27 February 2006; accepted 24 April 2006. Published: June 12, 2006.

Alterations in cellular metabolism are among the most consistent hallmarks of cancer. 
Herein we have investigated the relationship between increased aerobic lactate production and mitochondrial physiology in tumor cells. 
To diminish the ability of malignant cells to metabolize pyruvate to lactate, lactate dehydrogenase A (LDH-A) levels were knocked down by means of LDH-A short hairpin RNAs. 
Reduction in LDH-A activity resulted in stimulation of mitochondrial respiration and decrease of mitochondrial membrane potential. 
It also compromised the ability of these tumor cells to proliferate under hypoxia. 
The tumorigenicity of the LDH-A-deficient cells was severely diminished, and this phenotype was reversed by complementation with the human ortholog LDH-A protein. 
These results demonstrate that LDH-A plays a key role in tumor maintenance.

Copyright © 2006 Elsevier B.V.
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