蛋白磷酸酶2A抑制剂通过核因子-κB通路激活胰腺癌细胞外源性凋亡通路的机制  

Protein phosphatase 2A inhibitors activate extrinsic apoptosis in pancreatic cancer cells through nu-clear factor-κB dependent pathway

作　　者：李伟[1] 陈政[3] 龚斐然 苗毅[3] 徐泽宽[3] 陶敏[1] 

机构地区：[1]苏州大学附属第一医院肿瘤科,215006 [2]血液科 [3]南京医科大学第一附属医院普外科

出　　处：《中华实验外科杂志》2012年第11期2215-2218,共4页Chinese Journal of Experimental Surgery

基　　金：国家自然科学基金资助项目（81072031、81101867）;江苏省自然科学基金资助项目（BK2010585）;苏州市科教兴卫青年科技项目（SWKQl003、SWKQl011）

摘　　要：目的探讨蛋白磷酸酶2A（PP2A）抑制剂通过激活核因子-κB（NF-κB）通路诱导胰腺癌细胞株人胰腺癌细胞（PANC，1）凋亡的机制。方法荧光素酶报告基因检测NF．KB通路的激活水平，试剂盒检测半胱氨酰天冬氨酸特异性蛋白酶（Caspase）-8、9活性，逆转录-聚合酶链反应（RT-PCR）检测NF-κB通路下游凋亡相关基因表达水平。结果PP2A抑制剂斑蝥素、冈田酸可激活NF-κB通路，分别使NF-κB转录活性上升（10．11±4．09）倍、（16．21±5．75）倍。NF-κB通路抑制剂Bay11-7082预处理，可分别使斑蝥素、冈田酸诱导的NF-κB转录活性上升幅度下降（61．19±6．08）％、（62．09±12．38）％；斑蝥素、冈田酸可激活外源性凋亡通路，分别使Caspase-8活性上升（0．55±0．12）倍、（0．85±0．21）倍。Bay11-7082预处理，可分别使斑蝥素、冈田酸诱导的Caspase-8活性上升幅度下降（20．99±7．13）％、（29．07±7．98）％；斑蝥素、冈田酸可激活内源性凋亡通路，分别使Caspase-9活性上升（1．35±0．20）倍、（1．18±0．19）倍，但Bay11-7082预处理，对斑蝥素、冈田酸诱导的Caspase-9活性上升幅度无明显影响；斑蝥素、冈田酸可上调促凋亡基因的表达；Bay11-7082预处理可抑制斑蝥素、冈田酸诱导的促凋亡基因表达上调。结论PP2A抑制剂通过NF-κB通路依赖性机制激活胰腺癌细胞外源性凋亡通路，并上调促凋亡基因的表达。Objective To investigate the apoptosis induction effect of protein phosphatase 2A （PP2A） inhibitors on human pancreatic cancer cell line （PANC-1）. Methods Activity of nuclear factor-κB （NF-κB） pathway was tested by using luciferase reporter gene assay. Activities of Caspase 8 and 9 were determined by kits. The expression levels of genes downstream of the NF-κB pathway were tested by u- sing reverse transcription-polymerase chain reaction （RT-PCR）. Results Treatment with PP2A inhibitors, eantharidin and Okadaic acid, up-regulated the transcriptional activity of NF-κB by the folds of 10. 11 ±4.09, and 16. 21 ± 5.75 respectively. Pretreatment with the NF-κB pathway inhibitor, Bay 11-7082, repressed the up-regulation of NF-κB transcriptional activity by （61.19 ± 6.08 ）% and （62.09 ± 12. 38 ）% respectively. Treatment with cantharidin or Okadaic acid activated extrinsic apoptosis pathway, and up-regu- lated the activity of Caspase 8 by the folds of 0. 55 ±0. 12, and 0. 85±0. 21 respectively. Pretreatment with Bay 11-7082 repressed the up-regulation of Caspase 8 activity by （20. 99 ±7. 13）% and （29. 07±7.98）% respectively. Treatment with cantharidin or Okadaic acid also activated intrinsic apoptosis pathway, and up-regulated the activity of Caspase 9 by the folds of 1.35±0. 20, and 1.18 ±0. 19 respectively. However, pretreat- ment with Bay 11-7082 presented no significant effect on the up-regulation of Caspase 9 activity. Treatment with cantharidin or Okadaic acid up-regnlated the expression of pro-apoptotic genes which could be repressed by the pretreatment with Bay 11-7082. Conclusion PP2A inhibitors triggered extrinsic apoptosis and up-regulated the expressions of pro-apoptotic genes in pancreatic cancer cells through NF-κB dependent pathway.

关 键 词：胰腺癌 蛋白磷酸酶2A 斑蝥素 核因子-ΚB 

分 类 号：R735.9[医药卫生—肿瘤]