Mechanism Of The Sphingosine-1-phosphate Pathway With Related Inhibitors On The Malignant Biological Behaviors Of Pancreatic Cancer

Objective:S1P(Sphingosine-1-phosphate)pathway is an important part among the mechanisms of tumor malignant behaviors' regulations.Its ability on regulations of pancreatic cancer's invasion and metastasis is still unclear.As important molecules which play important roles in regulating tumor malignant behavior,whether ABL2 and N-Cadherin expressions are related to the activation of S1 P remains to be studied.As an ABL2 kinase inhibitor which is used on leukemia therapy in our research,The effections of nilotinib on the pancreatic cancer's proliferation,migration and invasion abilities are also important parts of our observations.Methods:Stimulate human pancreatic cancer PANC-1 cells with S1 P in vitro.Wound healing test and transwell were applied to observe the changes of migration and invasion.Then block S1PR1/3(S1Preceptor)through VPC23019.Use RT-PCR and Western Blot to detect the expressions of ABL2 and N-Cadherin,which were key molecules of migration and invasion..We applied ABL2 kinase inhibitor nilotinib in pancreatic cancer cell lines and used CCK-8 ? flow technology to detect the cytotoxicity of nilotinib.Combined application of S1 P and nilotinib on PANC-1 led to changes on cell migration,as well as the expressions of ABL2 and N-Cadherin,these changes were also key points of our research.Results:Wound healing assay and Transwell suggested that after S1 P stimulation on PANC-1,migration distance and the number of transmembrane cells were increased(P <0.05).As stimulating concentration increased,mRNA expression of ABL2 were positively correlated with S1 P concentrations after PANC-1 was stimulated,but N-Cadherin mRNA expression variation was a bell curve.When S1 P stimulating concentration was 100nmol/L,expressions of ABL2 and N-Cadherin were also increased(P<0.05).After PANC-1were blocked by VPC23019,migration and invasion ability,aswell as expressions of ABL2 ? N-Cadherin,were inhibited.Nilotinib(ABL2 kinase inhibitor)stimulating concentrations were positive correlated with cell line apoptosis rate,and could effectively inhibit S1P-induced increased migration ability,but also reduce the expression ofN-Cadherin.Conclusion:1?S1P could significantly enhance the expression of ABL2 and N-Cadherin and improve the ability of migration and invasion of PANC-1.This effection of S1 P could be blocked by specific S1PR1 / 3 receptor inhibitors VPC230192?Nilotinib(ABL2 kinase inhibitor)could effectively induce PANC-1 apoptosis and inhibit S1P-induced increased migration ability.The high expression of N-Cadherin which could be inhibited by nilotinib,ABL2 might regulate gene upstream of N-Cadherin.This situation might be associated with the regulation of S1 P signaling pathway.