p53抑制干细胞的自我更新能力而增敏奥沙利铂诱导肺癌细胞凋亡的作用及机制  

p53 sensitized lung cancer cells to oxaliplatin induced apoptosis through exerting repression on cancer stem cells renewal

作　　者：魏辉[1] 张勇[2] 江静[1] 贾奇[1] 罗璐[1] 任宏[3] 

机构地区：[1]陕西中医药大学附属医院肿瘤四科,陕西咸阳7120002 [2]宝鸡市中医医院胸外科,陕西宝鸡721000 [3]西安交通大学医学院第一附属医院胸外二科,陕西西安710016

出　　处：《现代肿瘤医学》2016年第22期3517-3523,共7页Journal of Modern Oncology

基　　金：国家自然科学基金资助项目(编号:81272418)

摘　　要：目的:研究p53通过增加肿瘤干细胞不等向分裂的比例而增敏奥沙利铂(Oxaliplatin,L-OHP)诱导肺癌细胞凋亡的作用及机制,探索影响肺癌化疗效果的因素。方法:用Nutlin-3(N-3)调控肺癌细胞野生型p53的表达,研究p53对L-OHP诱导细胞凋亡及对肺癌干细胞不同分裂模式的影响;使用Akt激活剂及shRNA-GSK3β调控表达的肺癌细胞系,研究p53通过Akt调控奥沙利铂诱导的肺癌细胞凋亡,并抑制肺癌干细胞自我更新能力。在肺癌标本中检测GSK3β与磷酸化Akt1的表达及与预后的关系。结果:Nutlin-3上调了A549及H460细胞中野生型p53的表达,有效抑制了细胞增殖,增强L-OHP诱导细胞凋亡效果。Nutlin-3抑制磷酸化Akt1,促进肺癌干细胞不等向分裂,进而抑制肿瘤干细胞的比例,增敏L-OHP诱导肺癌细胞凋亡。Akt1磷酸化活性在p53介导的下游GSK3β表达增加的调控中起关键作用。50nmol/L的L-OHP通过抑制Akt1活性促进凋亡,10μmol/L的Nutlin-3对L-OHP诱导的肺癌细胞凋亡有协同作用,是通过共同调控Akt1/GSK3β通路的活性实现,Akt1的激活与GSK3β的抑制均显著地抵消了p53对L-OHP诱导的肺癌干细胞比例降低。结论:p53通过抑制磷酸化Akt1的水平调控GSK3β表达,促肺癌干细胞不均等分裂,增敏L-OHP诱导凋亡。肺癌中GSK3β的高表达与磷酸化Akt1的低表达预示较好的临床治疗效果。Objective： To explore the functions of p53 in the regulations of the division manners of lung cancer stem cells（ CSCs）,which may therefore influence the Oxaliplatin（ L- OHP） induced apoptosis of lung cancer cells.Methods： The upregulation of p5 3 was achieved by using Nutlin- 3（ N- 3）,to testify its roles in controlling division manners and apoptosis of lung cancer stem cell. The A549 and H460 cells with increased p53 were treated with Akt1 activator and shRNA- GSK3β respectively,to study the functions of p53 in the cancer cell apoptosis induced by the L- OHP and explored the roles of p53 / Akt1 / GSK3β pathways in regulation of lung cancer stem cell apoptosis and self- renewal. We detected GSK3β and p- Akt1 expression in the lung cancer specimens and analyzed the correlation between their expressions. Results： The up- regulation of p53 stimulated cells apoptosis induced by L- OHP,and p53 inhibited cell proliferation through inducing more asymmetric cell division（ ACD） of lung cancer stem cells. The repression of p- Akt induced by N- 3 promoted the ACD in lung CSCs,and then decreased lung CSCs proportion. 50 nmol / L of L- OHP induced cell apoptosis through inhibiting Akt activity. 10μmol / L of N- 3 enhanced L- OHP induction of cell apoptosis by the way of regulating Akt1 / GSK3β pathways. Conclusion： p53 stimulates L- OHP induction of lung cancer cell apoptosis and the ACD in lung CSCs through the regulation of p53 / Akt /GSK3β pathways. The low expression of GSK3β and increased p- Akt levels in clinical tissue associated with the development of lung cancer.

关 键 词：肺癌 P53 AKT1 GSK3β 奥沙利铂 肺癌干细胞 

分 类 号：R734.2[医药卫生—肿瘤]