The Effect Of Monoacylglycerol Lipase Inhibi-Tor JZL184on The Proliferation Apoptosis And Migration Of Colorectal Cancer Cells And Its Mechanism

Background: Fat metabolism and lipid molecules are closely related with tumor. Mo-noacylglycerolLipase (MAGL) is involved in the decomposition of triacylglycerol (TAG) into free fatty acids (FFAs). Resent research shows that MAGL regulates the fatty acid network to enhance the pathogenicity and invasiveness of tumor cells. And after inhibited the gene or activity, the expressions of some lipid molecules such as lipid lysophosphatidic (LPA), prostaglandin E2(PGE2), were change with FFAs levels. MAGL-FFAs pathway regulates fatty acid network to affect tumor invasiveness, and MAGL is the key node in this path-way. MAGL was highly expressed in colorectal cancer tissues and inhibited the gene expression and activity of MAGL will lead that proliferation decreased, apoptosis increased, cell cycle arrested, the capacity invasion decreased in colorectal cancer cells, which may be associated with the expression of Cyclin D1and Bcl-2. But the relationship of apoptosis and nmigration remains between MAGL and colorectal cancer is not clear. This study was designed to explore the influence that inhibited with JZL184, MAGL affect proliferation and migration in colorectal cancer cells with JZL184inhibition and to find a new therapeu-tic target and treatment methods for colorectal cancer.Objective:To investigate the effect and mechanisms that MAGL inhibitor JZL184inter-vened the proliferation, apoptosis, migration, and drug sensitivity of chemotherapy.Methods:The proliferation of intervening with JZL184, JZL184combined with5-FU and5-FU alone in SW480, Lovo, HCT116human colorectal cancer cell lines was analyzed us-ing MTT. The apoptosis of intervening with JZL184, JZL184combined with5-FU and5-FU alone in colorectal cancer cells was analyzed by Flow Cytometry Methods. The mi-gration of colorectal cancers with JZL184intervening was assessed by Transwell method. Treat with JZL184and DMSO; the expressions of Bcl-2and Bax were detected with Real-time PCR and Western-blot in SW480,Lovo and HCT116. The expressions of EMT related proteins were detected with Western-blot in SW480and SW620which had different metastatic potential. The protein levels of p-AKT, p-mTOR, pro-Caspase3and pro-Caspase 8were detected with Western-blot in SW480and Lovo.Result: JZL184decreased the proliferation and induced the apoptosis in SW480,Lovo and HCT116human colorectal cancer cell lines.JZL184combined with different concertration of5-FU signifacantly increased the proliferation and decreased the apoptosis than5-FU alone. Then, we used JZL184intervene the different metastatic potential colorectal cancer cells SW480and SW620and found that JZL184was inhibited the migration of these can-cer cells, moreover, the decrease of migration in SW620was more than SW480. AT last, assessing by Real-time PCR and Western-blot, the levels of gene and protein in BCL-2was decreased and the expression of Bax was increased. And the protein levelof E-cardherin increased. The expression of pro-Caspase8, pro-Caspase3, Vimentin and Snail decreased.Conclusion: JZL184decreased the proliferation and migration, but induced apoptosis in colorectal cacner cells. The mechanism may be that JZL184regulated apoptosis related proteins BCL-2/Bax and pro-Caspase8/pro-Caspase3expressions, and influence the EMT-associated protein expression to inhibit tumor cell migration. Moreover, JZL184de-creased the expressions of p-AKT and p-mTOR to inhibit AKT-mTOR pathway to affect apoptosis and metastasis in colorectal cancer cell lines. Thus, JZL184might regulate the apoptosis related protein and EMT related protein through AKT-mTOR pathway.