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.

Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing

“…The enteroprotective effect of PEA passes through the direct or indirect activation of PPAR-α and CB2 receptors [138][139][140][144][145][146][147], whose expression has also been confirmed in the canine and feline gastrointestinal tract [101,109]. It has also recently been found that PEA restores the intestinal barrier permeability via the regulation of intercellular junctions [139,146,[148][149][150], and reduces inflammatory cell recruitment, i.e., macrophages and neutrophils, during experimental intestinal injury [138,144,147,[151][152][153][154]. PEA administration also decreased viral-induced diarrhea [140] and normalized intestinal motility in a post-inflammatory accelerated transit model [145].…”

Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice

“…PEA exerts potent anti-inflammatory effects, and it has been shown to improve intestinal inflammation, following both intraperitoneal and oral administration [ 5 ], in animal models of colitis. More importantly, its efficacy has also been demonstrated in mucosal biopsies from patients with ulcerative colitis (UC) [ 6 , 7 , 8 ], with the peroxisome proliferator activated receptor α (PPARα) being one of the key receptors mediating these effects [ 9 ].…”

Maintenance BEZ235 Treatment Prolongs the Therapeutic Effect of the Combination of BEZ235 and Radiotherapy for Colorectal Cancer

“…In addition to its pivotal role in hypoxia-mediated radioresistance, HIF-1α promotes tumor recurrence after RT by increasing tumor repopulation and protecting tumor blood vascular structure via VEGF production [34,47]. Indeed, the mTOR signaling pathway not only increases HIF-1α synthesis, but also promotes tumor angiogenesis in CRC cells [48,49,50]. In this study, we observed that BEZ235 and RT treatments followed by BEZ235 maintenance treatment significantly downregulated VEGF-A and HIF-1α expression in CRC cell lines and xenograft tumor tissue.…”