摘要
目的探讨外源性IL-8诱导卵巢癌细胞对顺铂和紫杉醇产生耐药的机制及相关信号转导通路。方法在原工作基础上,以两种人卵巢癌细胞系A2780(不分泌IL-8,对顺铂、紫杉醇敏感)和SKOV-3(高分泌IL-8,对顺铂、紫杉醇耐药)为研究模型,观察外源性IL-8是否影响卵巢癌细胞对顺铂和紫杉醇的敏感性,并对其作用的机制和可能的信号转导通路进行研究。结果①体外经IL-8处理的A2780细胞对顺铂和紫杉醇的敏感性均明显降低即产生部分耐药(耐药倍数分别为6.07和7.23),其耐药程度均低于IL-8高表达的SKOV-3细胞(耐药倍数分别为8.22和9.03)。②IL-8可以剂量依赖的方式上调A2780和SKOV-3细胞的耐药相关基因MDR1和凋亡抑制基因Bcl-2、Bcl-xL及XIAP的表达。③MEK1/2抑制剂和PI3K抑制剂均能阻断IL-8诱导的卵巢癌细胞对顺铂和紫杉醇产生的耐药。结论IL-8-很可能通过上调耐药相关基因MDR1和凋亡抑制基因Bcl-2、Bcl-xL及XIAP的表达而致卵巢癌细胞对顺铂和紫杉醇产生耐药。IL-8的上述作用是由Ras/Raf/MEK/MAPK和PI3K/Akt信号通路介导的。
In this study,we aimed to discover the mechanism of cisplatin and paclitaxel resistance caused by exogenous IL-8 in ovarian cancer cells and its related signal pathways.Based on our previous studies,the effect of exogenous IL-8 on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells was investigated.Meanwhile,we also investigated the mechanism of cisplatin and paclitaxel resistance caused by exogenous IL-8 in ovarian cancer cells and its related signal pathways.A2780,which do not express IL-8 and sensitive to cisplatin and paclitaxel,and SKOV-3 cells,which constitutively express high levels of IL-8 and resistant to cisplatin and paclitaxel,are suitable models for this study.We found that pretreatment of A2780 cells with IL-8 caused 6.07-fold and 7.23-fold increase in resistance to cisplatin and paclitaxel,respectively,whereas SKOV-3 cells exhibited 8.22-fold and 9.03-fold increase,respectively. IL-8 enhanced the expression of drug resistance-associated gene MDR1 and apoptosis-inhibiting genes（Bcl-2, Bcl-xL and XIAP） in A2780 and SKOV-3 cells.Pretreatment of A2780 cells with MEK1/2 or PI3K inhibitors blocked IL-8-induced cisplatin and paclitaxel resistance.These data suggest that IL-8 may confer cisplatin and paclitaxel resistance in ovarian cancer cells by increasing expression of drug resistance-associated gene MDR1 and apoptosis-inhibiting genes Bcl-2,Bcl-xL and XIAP.These activity of IL-8 is dependent on Ras/Raf/MEK/MAPK and PI3K/Akt signal transduction pathways.
出处
《免疫学杂志》
CAS
CSCD
北大核心
2010年第4期299-303,共5页
Immunological Journal
基金
天津市自然科学基金项目(08JCYBJC06900)
武警医学院科学技术研究重点项目(WJZ2007-1)
中国博士后科学基金面上项目(200804441177)
关键词
IL-8
卵巢癌细胞
顺铂和紫杉醇耐药
信号转导通路
IL-8
Ovarian cancer cells
Cisplatin and paclitaxel resistance
Signal transduction pathway
