BRD4抑制剂JQ1联合醋酸甲羟孕酮对子宫内膜癌细胞增殖和凋亡的影响  

Effects of combination of BRD4 inhibitor JQ1 and Medroxyprogesterone acetate on proliferation and apoptosis of endometrial cancer cells

作　　者：张丽华[1] 林千涵 庞迎新 Zhang Lihua;Lin Qianhan;Pang Yingxin(Department of Obstertrics and Gynecology,Qilu Hospital,Cheeloo College of Medicine,Shandong University,Jinan 250012)

机构地区：[1]山东大学齐鲁医院妇产科,济南250012

出　　处：《现代妇产科进展》2021年第5期360-364,共5页Progress in Obstetrics and Gynecology

基　　金：国家自然科学基金青年基金(No:81902657)。

摘　　要：目的:探讨BRD4抑制剂JQ1与醋酸甲羟孕酮(MPA)单独或联合作用对子宫内膜癌细胞增殖和凋亡的影响。方法:JQ1与MPA单独或联合作用于孕激素敏感的子宫内膜癌Ishikawa细胞和孕激素不敏感的子宫内膜癌HEC-1A细胞。MTT法和流式细胞仪检测药物对子宫内膜癌细胞的增殖抑制作用和凋亡作用。Western blot法检测凋亡相关蛋白cleaved caspase 3、PARP、cleaved PARP及mTOR/Akt通路等相关蛋白的表达。利用siRNA沉默BRD4后,MTT法检测BRD4 siRNA与MPA联用对子宫内膜癌细胞的生长抑制作用。结果:在孕激素敏感的Ishikawa细胞中,与对照组比较,JQ1组、MPA组、JQ1+MPA组的细胞增殖率显著降低(P均<0.05),其中JQ1+MPA组的细胞增殖率最低,析因分析提示JQ1与MPA有交互作用(P<0.05);JQ1组、MPA组、JQ1+MPA组的细胞凋亡率显著增加(P均<0.05),凋亡相关蛋白变化明显,其中JQ1+MPA组的细胞凋亡率增加最为显著(P<0.05),凋亡相关蛋白变化最大。利用siRNA沉默BRD4后观察联合MPA的作用显示,与对照组比较,BRD4 siRNA组、MPA组、BRD4 siRNA+MPA组的细胞增殖率显著降低(P均<0.05),其中BRD4 siRNA+MPA组的细胞增殖率最低。结论:BRD4抑制剂JQ1联合MPA对孕激素敏感的子宫内膜癌细胞有较好的增殖抑制及凋亡作用,其可能机制与抑制mTOR/AKT通路有关。Objective:To investigate the effects of BRD4 inhibitor JQ1 or Medroxyprogesterone acetate(MPA)alone and combination on proliferation and apoptosis of endometrial cancer cells in vitro.Methods:Progestin-sensitive endometrial cancer cells Ishikawa and progestin-resistance HEC-1A cells were exposed to JQ1 or MPA alone and combination.Cell proliferation rates and cell apoptosis rates were measured by MTT and flow cytometry analysis.Apoptosis related proteins and mTOR/Akt pathway proteins were determined by Western blot analysis.Using BRD4 siRNA to downregulate expression of BRD4,MTT assay determined the proliferation rate with the combination of MPA in Ishikawa cells.Results:In progestin-sensitive Ishikawa cells,compared with the control group,JQ1,MPA and JQ1+MPA groups showed remarkably decreased cell proliferation rate(P<0.05),and JQ1+MPA group had the most significant cell proliferation inhibition effect(P<0.05).The apoptosis rate in JQ1,MPA and JQ1+MPA groups all significantly increased(all P<0.05),and JQ1+MPA group showed the highest apoptosis rate compared with JQ1 and MPA group(P<0.05).In Ishikawa cells,accompanied by increased activation of caspase 3 and cleavage of poly(adenosine diphosphate[ADP]-ribose)polymerase 1(PARP).We showed that typical mTOR/AKT signaling was involved in JQ1 and MPA-mediated cell death.After down-regulation of BRD4 by siRNA,compared with the control group,BRD4 siRNA,MPA and BRD4 siRNA+MPA groups showed remarkably decreased cell proliferation rate(P<0.05),and BRD4 siRNA+MPA group had the most significant cell proliferation inhibition effect(P<0.05).Conclusions:Combination of BRD4 inhibitor JQ1 and MPA suppresses cell proliferation and induces apoptosis in progestin-sensitive cancer cells potentially by inhibiting the mTOR/AKT signaling pathway.

关 键 词：子宫内膜癌 JQ1 BRD4 醋酸甲羟孕酮 mTOR/Akt通路 

分 类 号：R737[医药卫生—肿瘤]