基于IRE1α/CREB/NLRP1通路探讨青蒿琥酯抑制慢性粒细胞白血病细胞生长的作用机制  

Discussion on Mechanism of Artesunate Inhibiting Growth of Chronic Myeloid Leukemia Cells Based on IRE1α/CREB/NLRP1 Pathway

作　　者：罗曼[1] 胡莉文[1] 古学奎[1] 杨洪涌[1] LUO Man;HU Liwen;GU Xuekui;YANG Hongyong

机构地区：[1]广州中医药大学第一附属医院血液科,广东广州510405

出　　处：《新中医》2020年第15期1-6,共6页New Chinese Medicine

基　　金：广州中医药大学创新基金项目(09CX035)。

摘　　要：目的:基于内质网应激相关的跨膜蛋白激酶1α(IRE1α)/环磷腺苷效应元件结合蛋白(CREB)/NOD样受体1(NLRP1)通路探讨青蒿琥酯(ART)促进慢性粒细胞白血病(CML)细胞生长抑制、诱导凋亡的作用。方法:分别用浓度为0μg/mL、12.5μg/mL、25.0μg/mL、50.0μg/mL的ART干预K562细胞后,观察细胞生存情况和增殖活性,细胞凋亡后周期分布,谷胱甘肽(GSH)与活性氧(ROS)含量变化及IRE1α/CREB/NLRP1的表达量。结果:与对照组比较,12.5~50μg/mL浓度的ART可以显著抑制K562细胞的增殖、生长,诱导细胞凋亡(P<0.01);还可以使K562细胞内总GSH、GSH水平,谷胱甘肽还原酶(GSH-Rd)、谷胱甘肽过氧化物酶(GSH-Px)活力降低(P<0.05),ROS含量增加(P<0.05),IRE1α、p-CREB mRNA和蛋白表达下降(P<0.05),25.0μg/mL组、50.0μg/mL组CREB mRNA和蛋白表达增加(P<0.05),但对NLRP1 mRNA和蛋白表达均无显著影响。与12.5μg/mL的ART比较,50.0μg/mL的ART可使K562细胞内总GSH、GSH水平,GSH-Rd、GSH-Px活力,IRE1α、p-CREB mRNA和蛋白表达降低(P<0.05),25.0μg/mL组、50.0μg/mL组CREB mRNA和蛋白表达增加(P<0.05)。结论:ART可显著抑制K562细胞的活力和增殖,诱导其凋亡,并显著降低细胞中GSH含量,升高ROS含量,且可能是通过IRE1α/CREB/NLRP1通路实现的。Objective:To investigate the role of artesunate(ART)in inhibiting the growth of chronic myeloid leukemia(CML)cells and inducing its apoptosis based on endoplasmic reticulum stress related inositol requiring enzyme 1α(IRE1α)/cAMP-response element binding protein(CREB)/NOD-like receptor 1(NLRP1)pathway.Methods:After intervening K562 cells by ART with the concentration of 0μg/mL,12.5μg/mL,25.0μg/mL,and 50.0μg/mL respectively,the cell survival and proliferative activity,the cycle distribution after cell apoptosis,the changes in the contents of glutathione(GSH)and reactive oxygen species(ROS),and the expressions of IRE1α/CREB/NLRP1 were observed.Results:Compared with those in the control group respectively,ART with the concentration of 12.5~50μg/mL could significantly inhibit the proliferation and growth of K562 cells and induce the apoptosis(P<0.01);the levels of total GSH and GSH,activity of glutathione reductase(GSH-Rd)and glutathione peroxidase(GSH-Px)in K562 cells was decreased(P<0.05);ROS content was increased(P<0.05);expressions of IRE1α,p-CREB mRNA and protein were decreased(P<0.05);expressions of CREB mRNA and protein were increased in the group of 25.0μg/mL ART and 50.0μg/mL ART(P<0.05);but there was no significant effect on expressions of NLRP1 mRNA and protein.Compared with 12.5μg/mL ART,50.0μg/mL ART can reduce the levels of total GSH and GSH,activity of GSH-Rd and GSH-Px as well as expressions of IRE1α,p-CREB mRNA and protein in K562 cells(P<0.05);the expressions of CREB mRNA and protein were increased in the group of 25.0μg/mL ART and 50.0μg/mL ART(P<0.05).Conclusion:ART can significantly inhibit the activity and proliferation of K562 cells,induce their apoptosis,significantly reduce the GSH contents in the cells and increase the ROS contents,which may be realized by IRE1α/CREB/NLRP1 pathway.

关 键 词：慢性粒细胞白血病 青蒿琥酯 内质网应激 细胞生长 细胞凋亡 

分 类 号：R733.72[医药卫生—肿瘤]