Inhibition of AKT abrogates chemotherapy-induced NF-κB survival mechanisms:: Implications for therapy in pancreatic cancer
Inhibition of AKT abrogates chemotherapy-induced NF-κB survival mechanisms:: Implications for therapy in pancreatic cancer
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DOI：
10.1016/j.jamcollsurg.2003.12.005
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发表时间：
2004-04-01
影响因子：
5.2
通讯作者：
Bold, RJ
中科院分区：
文献类型：
--
作者：
Fahy, BN;Schlieman, MG;Bold, RJ
背景：当核因子（NF）-κ B通路被激活时，它是一种抑制凋亡性细胞死亡的有效细胞信号。胰腺癌对化疗的凋亡效应具有抗性，尽管目前尚不清楚这是一种固有特征还是参与化疗的生存信号。我们研究了胰腺癌细胞是否会激活NF-kappaB途径来响应化疗，以及抑制这种反应是否会改变化疗的细胞凋亡功效。研究设计：我们使用物理（电泳迁移率变动分析）和功能（荧光素酶）技术测定了MIA-PaCa-2人胰腺癌细胞系化疗后的NF-kappaB活性。化疗对抗凋亡基因BCL-2（NF-κ B的靶基因）转录的影响被确定。我们研究了抑制Akt（NF-κ B的上游激活物）对化疗的分子（NF-κ B功能和BCL-2转录）和细胞（凋亡）效应的影响。结果：化疗药物吉西他滨和紫杉醇均激活NF-κ B并刺激BCL-2基因启动子活性。BCL-2启动子功能的刺激受NF-κ B直接调节。这些细胞反应被Akt的抑制所阻断。吉西他滨和紫杉醇的凋亡作用也增强Akt inhibition.CONCLUSIONS：胰腺癌的凋亡抵抗的一部分可能是通过激活NF-κ B生存途径介导的化疗反应。抑制这种反应可能是增加化疗疗效的重要辅助手段。(C)2004年由美国外科医生学会。
BACKGROUND: When activated, the nuclear factor (NF)-kappaB pathway is a potent cellular signal that inhibits apoptotic cell death. Pancreatic cancer is resistant to the apoptotic effect of chemotherapy, though it is unclear whether this is an inherent feature or a survival signal engaged in response to chemotherapy. We investigated whether pancreatic cancer cells activate the NF-kappaB pathway in response to chemotherapy and whether inhibition of this response altered the apoptotic efficacy of chemotherapy.STUDY DESIGN: We determined NF-kappaB activity after chemotherapy treatment of the MIA-PaCa-2 human pancreatic cancer cell line using both physical (electrophoretic mobility shift assay) and functional (luciferase) techniques. The effect of chemotherapy on transcription of the antiapoptotic gene BCL-2, a target of NF-kappaB, was determined. We examined the effect of inhibition of Akt, an upstream activator of NF-kappaB, on the molecular (NF-kappaB function and BCL-2 transcription) and cellular (apoptosis) effect of chemotherapy.RESULTS: Both the chemotherapeutic agents gemcitabine and paclitaxel activated NF-kappaB and stimulated BCL-2 gene promoter activity. The stimulation of BCL-2 promoter function was directly regulated by NF-kappaB. These cellular responses were blocked by inhibition of Akt. The apoptotic effect of gemcitabine and paclitaxel also was enhanced after Akt inhibition.CONCLUSIONS: Part of the apoptotic resistance of pancreatic cancer may be mediated by activation of the NF-kappaB survival pathway in response to chemotherapy. Inhibition of this response may be an important adjunct to increase the efficacy of chemotherapy. (C) 2004 by the American College of Surgeons.