Pro-Apoptotic Effects of Anandamide in Human Gastric Cancer Cells Are Mediated by AKT and ERK Signaling Pathways

被引：0

作者：

Garcia-Hernandez, Victor M. ^{[1
]}

Torres-Roman, Ana Laura ^{[1
]}

Ruiz-Garcia, Erika ^{[1
]}

Santamaria, Abel ^{[2
]}

Manzo-Merino, Joaquin ^{[3
]}

Garcia-Lopez, Alejandro ^{[4
]}

Angelica-Lezama, Ruth ^{[5
]}

Matus-Santos, Juan A. ^{[6
]}

Prospero-Garcia, Oscar ^{[7
]}

Navarro-Rios, Julian ^{[8
]}

Ortega-Gomez, Alette ^{[1
]}

机构：

[1] Natl Canc Inst, Translat Med Lab, SSA, Mexico City 14080, Mexico

[2] Metropolitan Autonomous Univ Xochimilco, Nanotecnol & Nanomed Lab, Mexico City 04960, Mexico

[3] Benemerita Univ Autonoma Puebla, Chem Sci Fac, Puebla 72570, Mexico

[4] Natl Inst Nutr & Med Sci Salvador Suviran, Biochem Unit, SSA, Mexico City 14080, Mexico

[5] Natl Polytech Inst IPN, Natl Sch Biol Sci, Cytol Lab, Mexico City 11340, Mexico

[6] Int Oncol Ctr COI, Mexico City 04700, Mexico

[7] Natl Autonomous Univ Mexico UNAM, Sch Med, Dept Physiol, Cannabinoids Lab, Mexico City 04510, Mexico

[8] Natl Canc Inst, Basic Invest Dept, SSA, Mexico City 14080, Mexico

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2025年 / 26卷 / 05期

关键词：

gastric cancer; anandamide; anti-proliferative; cannabinoids; apoptosis; ACTIVATED PROTEIN-KINASE; CANNABINOID RECEPTOR AGONISTS; ACID AMIDE HYDROLASE; GENE-EXPRESSION; CYCLE ARREST; WIN 55,212-2; C-MYC; PROLIFERATION; CANNABIDIOL; SURVIVAL;

D O I：

10.3390/ijms26052033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M) 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.

引用

页数：14

共 80 条

[1] Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin, 68, pp. 394-424, (2018)
[2] Pacher P., Kogan N.M., Mechoulam R., Beyond THC and Endocannabinoids, Annu. Rev. Pharmacol. Toxicol, 60, pp. 637-659, (2020)
[3] Maccarrone M., Di Rienzo M., Battista N., Gasperi V., Guerrieri P., Rossi A., Finazzi-Agro A., The Endocannabinoid System in Human Keratinocytes, J. Biol. Chem, 278, pp. 33896-33903, (2003)
[4] Laezza C., Pagano C., Navarra G., Pastorino O., Proto M.C., Fiore D., Piscopo C., Gazzerro P., Bifulco M., The Endocannabinoid System: A Target for Cancer Treatment, Int. J. Mol. Sci, 21, (2020)
[5] Hasenoehrl C., Taschler U., Storr M., Schicho R., The gastrointestinal tract–a central organ of cannabinoid signaling in health and disease, Neurogastroenterol. Motil, 28, pp. 1765-1780, (2016)
[6] Ligresti A., Bisogno T., Matias I., De Petrocellis L., Cascio M.G., Cosenza V., D'argenio G., Scaglione G., Bifulco M., Sorrentini I., Et al., Possible endocannabinoid control of colorectal cancer growth, Gastroenterology, 125, pp. 677-687, (2003)
[7] Ligresti A., Moriello A.S., Starowicz K., Matias I., Pisanti S., De Petrocellis L., Laezza C., Portella G., Bifulco M., Di Marzo V., Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma, J. Pharmacol. Exp. Ther, 318, pp. 1375-1387, (2006)
[8] McAllister S.D., Christian R.T., Horowitz M.P., Garcia A., Desprez P.-Y., Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells, Mol. Cancer Ther, 6, pp. 2921-2927, (2007)
[9] McAllister S.D., Murase R., Christian R.T., Lau D., Zielinski A.J., Allison J., Almanza C., Pakdel A., Lee J., Limbad C., Et al., Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis, Breast Cancer Res. Treat, 129, pp. 37-47, (2011)
[10] Ramer R., Bublitz K., Freimuth N., Merkord J., Rohde H., Haustein M., Borchert P., Schmuhl E., Linnebacher M., Hinz B., Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1, FASEB J, 26, pp. 1535-1548, (2011)

← 1 2 3 4 5 6 7 8 →