Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression

Anne Le, Charles R. Cooper, Arvin M. Gouw, Ramani Dinavahi, Anirban Maitra, Lorraine M. Deck, Robert E. Royer, David L. Vander Jagt, Gregg L. Semenza, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

Abstract

As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is notwellunderstood.Here,wereport that reduction ofLDHAby siRNAor its inhibition by asmall-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4- propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD+ synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.

Original languageEnglish (US)
Pages (from-to)2037-2042
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number5
DOIs
StatePublished - Feb 2 2010

Keywords

  • Glycolysis
  • Lymphoma
  • Pancreatic cancer
  • Redox stress
  • Xenograft models

ASJC Scopus subject areas

  • General

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