内质网应激激活P38通路诱导胃癌细胞对多柔比星产生耐药

摘要

目的:在二维及三维细胞培养模式下探讨内质网应激能否诱导胃癌细胞对多柔比星产生耐药及其可能机制.方法:本研究利用贴壁培养的胃癌细胞,采用流式细胞仪检测对照组、内质网应激诱导剂组、多柔比星组及内质网应激诱导剂加多柔比星组的细胞凋亡率;并检测P38通路受阻能否逆转内质网应激诱导胃癌细胞对多柔比星的耐药现象.利用前期建立的胃癌细胞三维培养模型,用流式细胞仪及live/dead assay进一步验证以上结果.结果:在贴壁培养模式下,与对照组相比,各药物处理组胃癌细胞的凋亡率均明显增高,多柔比星组细胞凋亡率显著高于内质网应激诱导剂加多柔比星组;且P38活化受阻可基本恢复内质网应激状态下胃癌细胞对多柔比星的敏感性.在三维培养模式下,流式细胞仪及live/deadassay检测结果与贴壁培养条件下一致.结论:在二维及三维培养模式下,内质网应激均可通过激活P38通路诱导胃癌细胞对化疗药物多柔比星产生耐药,阻断该通路可基本抑制内质网应激诱导胃癌细胞对该化疗药物的耐药现象.%Objective:To investigate the mechanism of the endoplasmic reticulum (ER) stress-induced chemoresistance to doxorubicin in BGC823 gastric cancer cells.Methods:Adherent gastric cancer cells were divided into untreated control group,ER stress inducer-treated group,doxorubicin-treated group and ER stress inducer plus doxorubicin-treated group.Whether ER stress could decrease the sensitivity of gastric cancer cells to doxorubicin was explored using flow cytometry.Whether ER stress-induced chemoresistance to doxorubicin could be abrogated by blocking P38 activity in gastric cancer cells was elucidated using flow cytometry.3-dimensional culture system previously established was used to confirm the above experiment by flow cytometry and live/dead assay.Results:Compared with the control group,the apoptotic rate of gastric cancer cells of all the treated group were significantly increased.Compared with the doxorubicin-treated group,the apoptotic rate of gastric cancer cells of ER stress inducer plus doxorubicin-treated group was greatly decreased.Inhibition of P38 activity could overcome ER stress-induced chemoresistance to doxorubicin in gastric cancer cells.Conclusion:ER stress could trigger the chemoresistance to doxorubicin via the activation of P38 in BGC823 gastric cancer cells under both 2-dimensional and 3-dimensional culture systems.