The Promoting Effect Of Targeting SHCBP1 On Apatinib Inhibiting Tumor Angiogenesis

Objective: Apatinib,an anti-angiogenic drug,is an important targeted drug for gastric cancer treatment.However,the sensitivity of apatinib on angiogenesis is not enough for clinic therapy on gastric cancer.The purpose of this study is to explore the role of SHCBP1 in apatinib-inhibited angiogenesis of gastric cancer,providing theoretical basis for developing new synergistic therapies of apatinib for gastric cancer.Methods: Firstly,8 human umbilical vein endothelial cells were isolated from different donors,and endothelial lines with insufficient sensitivity to apatinib were screened by tube formation assay.Then the correlation between the expression of SHCBP1 and apatinib sensitivity was verified by western blotting.To investigate the effect of SHCBP1 knockout on the effect of apatinib to inhibit angiogenesis,SHCBP1 knockout human vascular endothelial cells and Shcbp1 knockout mouse aortas cultured in vitro were used as models.Subsequently,the best inhibitor targeting SHCBP1-PLK1 complex was screened from Theaflavine-3,3’-digallate(TFBG)and its structural analogues by virtual screening and microscale thermophoresis.Finally,the effect of inhibitor on inhibiting angiogenesis and gastric cancer was verified by endothelial cell proliferation,tube formation assay,chick embryo choriallantoic membrane model and xenograft tumor model of gastric cancer cells.Results: The expression of SHCBP1 was significantly higher in vascular endothelial lines with poor angiogenesis sensitivity of apatinib,and the expression level of SHCBP1 was negatively correlated with apatinib sensitivity.Compared with wild type,SHCBP1 knockout vascular endothelial cells and mouse aortic rings were more sensitive to the inhibition of angiogenesis by apatinib.Subsequently,the best inhibitor targeting SHCBP1-PLK1 complex was selected as TFBG by virtual screening and microscale thermophoresis.Vascular endothelial cell proliferation,tube formation assay,chick embryo choriallantoic membrane model showed that TFBG could enhance the ability of apatinib to inhibit angiogenesis.The results of xenograft tumor model of gastric cancer cells showed that TFBG combined with apatinib could significantly inhibit the growth of gastric cancer.Conclusion: SHCBP1 can regulate the sensitivity of apatinib to inhibit tumor angiogenesis,and SHCBP1-PLK1 inhibitor TFBG can enhance the therapeutic effect of apatinib on gastric cancer by inhibiting angiogenesis.