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: Francisco J Caballero, Rafael Soler-Torronteras, Maribel Lara-Chica, Victor García, Bernd L Fiebich, Eduardo Muñoz, Marco A Calzado
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 746 Pg. 221-32 (Jan 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25460026 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Arachidonic Acids
• NF-kappa B
• NFATC Transcription Factors
• Neoplasm Proteins
• Nerve Tissue Proteins
• Recombinant Fusion Proteins
• Cyclooxygenase 2
• PTGS2 protein, human
• N-(4-hydroxyphenyl)arachidonylamide

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Arachidonic Acids (pharmacology)
• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (chemistry, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Reporter (drug effects)
• Humans
• Mice
• NF-kappa B (antagonists & inhibitors, metabolism)
• NFATC Transcription Factors (antagonists & inhibitors, metabolism)
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Nerve Tissue Proteins (antagonists & inhibitors, genetics, metabolism)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Promoter Regions, Genetic (drug effects)
• Recombinant Fusion Proteins (chemistry, metabolism)
• Signal Transduction (drug effects)