The Effects And Mechanisms Of Sanguinarine On Gastric Cancer Cells Proliferation And Invasion

Gastric cancer(GC)is a common malignant tumor of digestive system.It has the third highest lethality in all cancers worldwide.The 5-year survival rate of early GC is more than 95%,however,clinical diagnoses of gastric cancer often belong to advanced GC.The prognosis of advanced GC is poor,and the objective response rate of combined chemotherapy in advanced GC is unsatisfactory.Therefore,development of more effective chemotherapeutic agents to improve therapy for GC is urgently needed.Effective components of Chinese herbs in the treatment of GC has become a hot spot in recent years.Sanguinarine is a bioactive benzophenanthridine alkaloid found in plants of the Papaveraceae family.Previous studies have found that sanguinarine has broad spectrum pharmacological properties,including anti-oxidative,anti-inflammatory,anti-microbial,and anesthesia effect on the central nervous.Recently,its anti-cancer properties have been testified in various cancers,such as breast cancer,melanoma,prostate cancer,and so on.Some studies show that DUSP4 is significantly upregulated by sanguinarine in pancreatic cancer cells,suggesting that sanguinarine may act as the DUSP4 activator exerting its activity in cancer.However,the therapeutic effects and regulatory mechanisms of sanguinatine in gastric cancer remain elusive.The present study was aimed to investigate the correlation of dual specificity phosphatase 4(DUSP4)expression with clinicopathologic features and overall survival in GC patients and explore the effects of sanguinarine on tumor growth and invasion in GC cells(SGC-7901 and HGC-27)and underlying molecular mechanisms.Immunohistochemical analysis showed that decreased DUSP4 expression was associated with the sex,tumor size,depth of invasion and distant metastasis in GC patients.Functional experiments including CCK-8,Transwell and Flow cytometry analysis indicated that sanguinarine or DUSP4 overexpression inhibited GC cell viability and invasive potential,and induced cell apoptosis and cycle arrest in S phase,but DUSP4 knockdown attenuated the antitumor activity of sanguinarine.Further observation demonstrated that sanguinarine upregulated the expression of DUSP4 but downregulated phosphorylated extracellular signal-regulated kinase(p-ERK),proliferating cell nuclear antigen(PCNA),matrix metalloproteinase 2(MMP-2)and B-cell lymphoma 2(Bcl-2)expression.Taken together,our findings indicate that sanguinarine inhibits growth and invasion of GC cells through regulation of the DUSP4/ERK pathway,suggesting that sanguinarine may have potential for use in GC treatment.