title: Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells.
abstract: For gastric cancers, the antineoplastic activity of cannabinoids has been investigated in only a few reports and knowledge regarding the mechanisms involved is limited. We have reported previously that treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis. Here, we evaluated the effects of cannabinoids on various cellular mediators involved in cell cycle arrest in gastric cancer cells. AGS and MKN-1 cell lines were used as human gastric cancer cells and WIN 55,212-2 as a cannabinoid agonist. Cell cycles were analyzed by flow cytometry and western blotting. Treatment with WIN 55,212-2 arrested the cell cycle in the G0/G1 phase. WIN 55,212-2 also upregulated phospho-ERK1/2, induced Kip1/p27 and Cip1/WAF1/p21 expression, decreased cyclin D1 and cyclin E expression, decreased Cdk 2, Cdk 4, and Cdk 6 expression levels, and decreased phospho-Rb and E2F-1 expression. ERK inhibitor decreased the proportion of G0/G1 phase which was induced by WIN 55,212-2. Inhibition of pAKT led to cell cycle arrest in gastric cancer cells. Cell cycle arrest preceded apoptotic response. Thus, this cannabinoid agonist can reduce gastric cancer cell proliferation via G1 phase cell cycle arrest, which is mediated via activation of the MAPK pathway and inhibition of pAKT.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jae Myung
authors.initials: JM
authors.lastname: Park
authors.forename: Xiang-Shu
authors.initials: XS
authors.lastname: Xian
authors.forename: Myung-Gyu
authors.initials: MG
authors.lastname: Choi
authors.forename: Hyeyeon
authors.initials: H
authors.lastname: Park
authors.forename: Yu Kyung
authors.initials: YK
authors.lastname: Cho
authors.forename: In Seok
authors.initials: IS
authors.lastname: Lee
authors.forename: Sang Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: In-Sik
authors.initials: IS
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D048588:Benzoxazines; D002070:Butadienes; D002121:Calcium Channel Blockers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D009570:Nitriles; D016160:Retinoblastoma Protein; C113580:U 0126; D050760:Cyclin-Dependent Kinase Inhibitor p27; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3