Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13754-8. doi: 10.1073/pnas.0907300106. Epub 2009 Aug 3.


alpha-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Fatty Acids / chemistry
  • Folic Acid Antagonists / pharmacology
  • Humans
  • Jurkat Cells
  • Leucovorin / chemistry
  • Lipids / chemistry
  • Methotrexate / pharmacology
  • Neoplasms / drug therapy
  • Oleic Acids / chemistry*
  • Oleic Acids / pharmacology
  • Substrate Specificity
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / physiology*


  • 2-hydroxy-9-cis-octadecenoic acid
  • 2-hydroxyoleic acid
  • Antineoplastic Agents
  • Fatty Acids
  • Folic Acid Antagonists
  • Lipids
  • Oleic Acids
  • Tetrahydrofolate Dehydrogenase
  • Leucovorin
  • Methotrexate