title: AM404 inhibits NFAT and NF-κB signaling pathways and impairs migration and invasiveness of neuroblastoma cells.
abstract: N-Arachidonoylphenolamine (AM404), a paracetamol lipid metabolite, is a modulator of the endocannabinoid system endowed with pleiotropic activities. AM404 is a dual agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) and the Cannabinoid Receptor type 1 (CB₁) and inhibits anandamide (AEA) transport and degradation. In addition, it has been shown that AM404 also exerts biological activities through TRPV1- and CB₁ -independent pathways. In the present study we have investigated the effect of AM404 in the NFAT and NF-κB signaling pathways in SK-N-SH neuroblastoma cells. AM404 inhibited NFAT transcriptional activity through a CB₁- and TRPV1-independent mechanism. Moreover, AM404 inhibited both the expression of COX-2 at transcriptional and post-transcriptional levels and the synthesis of PGE₂. AM404 also inhibited NF-κB activation induced by PMA/Ionomycin in SK-N-SH cells by targeting IKKβ phosphorylation and activation. We found that Cot/Tlp-2 induced NFAT and COX-2 transcriptional activities were inhibited by AM404. NFAT inhibition paralleled with the ability of AM404 to inhibit MMP-1, -3 and -7 expression, cell migration and invasion in a cell-type specific dependent manner. Taken together, these data reveal that paracetamol, the precursor of AM404, can be explored not only as an antipyretic and painkiller drug but also as a co-adjuvant therapy in inflammatory and cancer diseases.
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Caballero
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Soler-Torronteras
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Lara-Chica
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: García
authors.affiliation: Department of Psychiatry, University of Freiburg Medical School, Freiburg, Germany.
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain. Electronic address: e.munoz@uco.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain. Electronic address: mcalzado@uco.es.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D001095:Arachidonic Acids; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C107594:N-(4-hydroxyphenyl)arachidonylamide
keywords: AM404; Acetaminophen; COX-2; NFAT; Neuroblastoma; Tpl2/Cot kinase