Pro-Apoptotic Effects of Anandamide in Human Gastric Cancer Cells Are Mediated by AKT and ERK Signaling Pathways
Por:
García-Hernández V.M., Torres-Román A.L., Ruiz-García E., Santamaría A., Manzo-Merino J., García-López A., Angélica-Lezama R., Matus-Santos J.A., Prospéro-García O., Navarro-Ríos J., Ortega-Gómez A.
Publicada:
1 ene 2025
Resumen:
Gastric cancer is one of the most common forms of cancer worldwide. A growing number of studies have addressed the anti-proliferative effects of cannabinoids on several tumor cells. The molecular mechanisms underlying the anti-proliferative effects of the endogenous cannabinoid anandamide (AEA) on gastric tumor cell lines have yet to be characterized. Here, we investigated the anti-proliferative mechanisms elicited by AEA on the AGS human gastric cancer cell line employing an Oncoprint database, Western blotting, and immunofluorescence. We observed that AEA (5 µM) inhibited phosphorylated AKT’s expression level. This point is relevant because AKT is mutated in AGS cells, according to Oncoprint. In addition, AEA induced the up-regulation of phosphorylated ERK and, in turn, inhibited Bcl-2 expression and activated pro-apoptotic signals induced by pro-apoptotic Bax and Bak, which resulted in caspase-3 activation. The effect of anandamide on phosphorylated AKT was dependent on cannabinoid receptor 2 activation (CB2R) as revealed by the selective inverse agonist JTE-907, which reverted the anandamide-induced expression in the phosphorylated AKT/total AKT ratio. In contrast, changes in phosphorylated ERK evoked an increase in pro-apoptotic pathways that culminated in cell death by caspase-3 activation. These results indicate that the endogenous cannabinoid anandamide in gastric cancer cells increases caspase-3 activity via mitochondrial pro-apoptotic Bax/Bak proteins and decreases viability through CB2R via AKT down-regulation’s trophic mechanisms. These effects constitute a promising tool for the design of gastric cancer therapies. © 2025 by the authors.
Filiaciones:
García-Hernández V.M.:
Translational Medicine Laboratory, National Cancer Institute, S.S.A., Mexico City, 14080, Mexico
Torres-Román A.L.:
Translational Medicine Laboratory, National Cancer Institute, S.S.A., Mexico City, 14080, Mexico
Ruiz-García E.:
Translational Medicine Laboratory, National Cancer Institute, S.S.A., Mexico City, 14080, Mexico
Santamaría A.:
Nanotecnology and Nanomedicine Laboratory, Metropolitan Autonomous University-Xochimilco, Mexico City, 04960, Mexico
Manzo-Merino J.:
Chemistry Science Faculty, Benemérita Universidad Autónoma de Puebla, Puebla, 72570, Mexico
García-López A.:
Biochemistry Unit, National Institute of Nutrition and Medical Science Salvador Suvirán, S.S.A, Mexico City, 14080, Mexico
Angélica-Lezama R.:
Cytology Laboratory, National School of Biological Sciences, National Polytechnic Institute (IPN), Mexico City, 11340, Mexico
Matus-Santos J.A.:
International Oncologic Center (COI), Mexico City, 04700, Mexico
Prospéro-García O.:
Cannabinoids Laboratory, Department of Physiology, School of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, 04510, Mexico
Navarro-Ríos J.:
Basic Investigation Department, National Cancer Institute, S.S.A., Mexico City, 14080, Mexico
Ortega-Gómez A.:
Translational Medicine Laboratory, National Cancer Institute, S.S.A., Mexico City, 14080, Mexico
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