达沙替尼提高胃癌细胞对肿瘤坏死因子相关凋亡诱导配体敏感性机制研究

Dasatinib increased the sensitivity of gastric cancer cells to TRAIL

目的探讨胃癌细胞中肝细胞生长因子受体(MET)活化的原因以及达沙替尼提高胃癌细胞对肿瘤坏死因子相关凋亡诱导配体(TRAIL)的敏感性。方法免疫印记法检测BGC823和MGC803胃癌细胞中MET、p-MET、Src、p-Src蛋白的表达,MTT法检测达沙替尼和TRAIL处理后胃癌细胞的增殖,免疫荧光法检测Src和MET之间的相互作用。结果 TRAIL作用BGC823和MGC803胃癌细胞后,诱导了Src和MET的磷酸化。Src激酶抑制剂达沙替尼预处理后,抑制了TRAIL诱导的Src和MET的磷酸化。TRAIL能明显提高BGC823胃癌细胞中Src和MET的结合,而达沙替尼联合TRAIL处理BGC823胃癌细胞,Src和MET的结合减少。与TRAIL和达沙替尼单纯用药比较,达沙替尼联合TRAIL对BGC823和MGC803胃癌细胞的增殖抑制作用增强,差异有统计学意义(P<0.05)。结论达沙替尼通过阻止Src与MET的结合进而抑制了Src与MET的活化,提高了胃癌细胞对TRAIL的敏感性。

Objective To investigate the reason of hepatocyte growth factor receptor（ MET） avtivation and dasatinib enhancement of tumor necrosis factor related apoptosis inducing ligand（ TRAIL） sensitivity in gastric cancer cells. Methods Protein expressions of MET,p-MET,Src and p-Src in were detected by Western blot in BGC823 and MGC803 gastric cancer cells. Cell proliferation was measured using MTT assay after the treatment of Dasatinib and TRAIL. The interaction between Src and MET was detected by immunofluorescence. Results Treatment with TRAIL in BGC823 and MGC803 gastric cancer cells induced the phosphorylation of Src and MET. Pretreatment with Src kinase inhibitor dasatinib prevented the phosphorylation of Src and MET. TRAIL significantly promoted the interaction of Src and MET in BGC823 gastric cancer cells. Treatment with dasatinib combined TRAIL,the interaction of Src and MET was reduced. Compared single use of dasatinib or TRAIL,the combination of dasatinib and TRAIL increased the proliferation inhibition of BGC823 and MGC803 gastric cancer cells（ P〈0. 05）. Conclusion Dasatinib increased the sensitivity of gastric cancer cells to TRAIL through inhibiting the activation and interaction of Src and MET.