Palmitoylethanolamide Exerts Antiproliferative Effect and Downregulates VEGF Signaling in Caco-2 Human Colon Carcinoma Cell Line Through a Selective PPAR-α-Dependent Inhibition of Akt/mTOR Pathway

Phytother Res. 2016 Jun;30(6):963-70. doi: 10.1002/ptr.5601. Epub 2016 Mar 1.

Abstract

Palmitoylethanolamide (PEA) is a nutraceutical compound that has been demonstrated to improve intestinal inflammation. We aimed at evaluating its antiproliferative and antiangiogenic effects in human colon adenocarcinoma Caco-2 cell line. Caco-2 cells were treated with increasing concentrations of PEA (0.001, 0.01 and 0.1 μM) in the presence of peroxisome proliferator-activated receptor-a (PPAR-α) or PPAR-γ antagonists. Cell proliferation was evaluated by performing a MTT assay. Vascular endothelial growth factor (VEGF) release was estimated by ELISA, while the expression of VEGF receptor and the activation of the Akt/mammalian target of rapamycin (mTOR) pathway were evaluated by western blot analysis. PEA caused a significant and concentration-dependent decrease of Caco-2 cell proliferation at 48 h. PEA administration significantly reduced in a concentration-dependent manner VEGF secretion and VEGF receptor expression. Inhibition of Akt phosphorylation and a downstream decrease of phospho-mTOR and of p-p70S6K were observed as compared with untreated cells. PPAR-α, but not PPAR-γ antagonist, reverted all effects of PEA. PEA is able to decrease cell proliferation and angiogenesis. The antiangiogenic effect of PEA depends on the specific inhibition of the AkT/mTOR axis, through the activation of PPAR-α pathway. If supported by in vivo models, our data pave the way to PEA co-administration to the current chemotherapeutic regimens for colon carcinoma. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: Caco-2 human adenocarcinoma cell line; Palmitoylethanolamide (PEA); angiogenesis; proliferation.

MeSH terms

  • Amides
  • Animals
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Proliferation
  • Colonic Neoplasms / drug therapy*
  • Down-Regulation / drug effects
  • Ethanolamines / chemistry*
  • Ethanolamines / therapeutic use
  • Humans
  • Neovascularization, Pathologic
  • PPAR alpha / metabolism*
  • Palmitic Acids / chemistry*
  • Palmitic Acids / therapeutic use
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Amides
  • Ethanolamines
  • PPAR alpha
  • Palmitic Acids
  • Vascular Endothelial Growth Factor A
  • palmidrol