Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

Cancer Biol Ther. 2013 Nov;14(11):1050-8. doi: 10.4161/cbt.26206. Epub 2013 Sep 6.

Abstract

The omega-3 polyunsaturated fatty acids (ω3PUFAs) are a class of lipids biologically effective for the treatment of inflammatory disorders, cardiovascular disease and cancer. Patients consuming a high dietary intake of ω3PUFAs have shown a low incidence of metabolic disorders, including cancer. Although the effects of ω3PUFAs intake was shown to be involved in the prevention and treatment of these diseases, the underlying molecular mechanisms involved are not well understood. Here, we show that ω3PUFA, docosahexaenoic acid (DHA) enhanced the tumor suppressor function of LKB1. We observed that when LKB1 expressing cells are treated with DHA, there is an increase in LKB1 activity leading to phosphorylation of AMPK and inhibition of mTOR signaling. Abrogation of LKB1 in MCF-7 cells by siRNA reversed this phenotype. Furthermore, cellular metabolism was altered and ATP levels were reduced in response to DHA treatment, which was further attenuated in cells expressing LKB1. More importantly, in mammary epithelial cells expressing LKB1, the rate of glycolysis was decreased as a result of diminished expression of glycolytic enzymes. Functionally, these events lead to a decrease in the migration potential of these cells. Overall, our discovery shows for the first time that LKB1 function is enhanced in response to ω3PUFA treatment, thereby resulting in the regulation of cell metabolism.

Keywords: DHA; LDH-A; LKB1; aerobic glycolysis; cancer; cell metabolism; glycolytic enzymes; hexokinase; mTOR signaling; omega-3 PUFA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement / drug effects
  • Docosahexaenoic Acids / pharmacology*
  • Glucose / metabolism
  • Glycolysis / drug effects*
  • HeLa Cells
  • Hexokinase / metabolism
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • MCF-7 Cells
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Kinase / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Docosahexaenoic Acids
  • L-Lactate Dehydrogenase
  • STK11 protein, human
  • Hexokinase
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Pyruvate Kinase
  • Protein-Serine-Threonine Kinases
  • Glucose