Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the leading cause of cancer-associated mortality worldwide; however, only limited therapeutic treatments are currently available. The present study aimed to investigate the effects of cannabinoids as novel therapeutic targets in HCC. In addition, the mechanism underlying the effects of a synthetic cannabinoid, WIN55, 212‑2, on the BEL7402 HCC cell line was investigated. The results demonstrated that WIN55, 212‑2 induced cell cycle arrest of the BEL7402 cells at the G0/G1 phase via cannabinoid receptor 2 (CB2)‑mediated downregulation of phosphorylated-extracellular signal-regulated kinases (ERK)1/2, upregulation of p27, and downregulation of cyclin D1 and cyclin‑dependent kinase 4. Furthermore, inhibition of CB2 with the CB2 antagonist AM630 abrogated WIN55, 212‑2‑induced cell cycle arrest. Inhibition of ERK1/2 also resulted in cell cycle dysregulation and cell cycle arrest at the G0/G1 phase, which subsequently resulted in cell growth inhibition. In addition, the present study detected a significant reduction in matrix metalloproteinase‑9, retinoblastoma protein and E2F1 expression, and migration inhibition by WIN treatment. These results suggested that cannabinoid receptor agonists, including WIN, may be considered as novel therapeutics for the treatment of HCC.
Department of Biochemistry, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
Dacai
D
Xu
Department of Biochemistry, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
Jianglin
J
Wang
School of Mathematics, South China University of Technology, Guangzhou, Guangdong 510640, P.R. China.
Zhenkang
Z
Zhou
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan, Guangdong 523376, P.R. China.
Zhiwei
Z
He
Department of Biochemistry, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
Qing
Q
Zhao
D000970:Antineoplastic Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone