title: Palmitic acid increases invasiveness of pancreatic cancer cells AsPC-1 through TLR4/ROS/NF-κB/MMP-9 signaling pathway.
abstract: Pancreatic cancer (PC) is an aggressive malady with proclivity for early metastasis. Overexpression of toll-like receptor 4 (TLR4) in pancreatic ductal adenocarcinoma, the most common type of pancreatic malignancy, correlates to tumor size, lymph node involvement, venous invasion and pathological stage. Lipopolysaccharides (LPS) are natural TLR4 ligands that have been shown to increase the invasive ability of PC cells. However, rapid inactivation of circulating LPS and low systemic absorption of inhaled LPS from the bronchoalveolar compartment make other agonists such as saturated fatty acids more suitable to be considered for TLR4-related cell invasiveness. Interestingly, PC risk was strongly associated to intake of saturated fat from animal food sources, in particular to consumption of saturated palmitic acid (PA). In the present study, we investigated the influence of PA on the invasive capacity of human PC cells AsPC-1. Using specific inhibitors, we found that PA stimulation of these tumor cells induced a TLR4-mediated cell invasion. Our results also indicate that the signaling events downstream of TLR4 involved generation of reactive oxygen species, activation of nuclear factor-kappa beta, and secretion and activation of matrix metalloproteinase 9 (MMP-9). Furthermore, PA stimulation decreased the levels of the micro RNA 29c (miR-29c). Of note, while inhibition of miR-29c increased MMP-9 mRNA levels, MMP-9 secretion and activation, and invasiveness, miR-29c mimic abrogated all these PA-stimulated effects. These results strongly suggest that miR-29c could be an attractive potential pharmacological agent for antitumoral therapy in PC.
authors.affiliation: CBRHC Research Center, Buenos Aires, Argentina.
authors.forename: Makena J
authors.initials: MJ
authors.lastname: Binker-Cosen
authors.affiliation: CBRHC Research Center, Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Richards
authors.affiliation: CBRHC Research Center, Buenos Aires, Argentina.
authors.forename: Brenda
authors.initials: B
authors.lastname: Oliver
authors.affiliation: Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.affiliation: CBRHC Research Center, Buenos Aires, Argentina.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Binker
authors.affiliation: CBRHC Research Center, Buenos Aires, Argentina; Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: licb@cbrhc.org.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Cosen-Binker
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019308:Palmitic Acid / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019308:Palmitic Acid; D020780:Matrix Metalloproteinase 9
keywords: Matrix metalloproteinase-9 (MMP-9); Micro RNA 29c (miR-29c); Nuclear factor-kappa beta (NF-κB); Pancreatic cancer invasion; Reactive oxygen species (ROS); Toll-like receptor 4 (TLR4)