title: 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.
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.
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sarnelli
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gigli
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Capoccia
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Iuvone
authors.affiliation: Laboratory for Enteric NeuroScience (LENS), Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: Carla
authors.initials: C
authors.lastname: Cirillo
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Seguella
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Nobile
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Pesce
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Esposito
mesh_terms: D000577:Amides; D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects; D004983:Ethanolamines / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D009389:Neovascularization, Pathologic; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000737:chemistry* / Q000627:therapeutic use; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000577:Amides; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; D042461:Vascular Endothelial Growth Factor A; C005958:palmidrol
keywords: Caco-2 human adenocarcinoma cell line; Palmitoylethanolamide (PEA); angiogenesis; proliferation