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Pretreatment with PKC Inhibitor enhances TNF-alpha induced apoptosis in TNF-aloha resistant cells and Enhancement of TNF induced antitumor activity by Inhibition of superoxide dismutase induction

PKC 抑制剂预处理可增强 TNF-α 诱导的 TNF-aloha 抗性细胞凋亡，并通过抑制超氧化物歧化酶诱导增强 TNF 诱导的抗肿瘤活性

基本信息

批准号：
14571649
负责人：
NISHIDA Shozo
金额：
$ 2.18万
依托单位：
Kinki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571649/
关键词：
TNFα PKC signal transdction drug resistance

项目摘要

Tumor necrosis factor α (TNF-α) modulate various events through several pathways. Many tumor cells are the resistance to this cytokine. Pretreatment of these cells with actinomyucin D enhances TNF-α induced apoptosis. We investigated the mechanism and whether or not apoptosis of TNF-α-resistant cancer cells can be induced by the inhibition of Protein kinase C (PKC). When TNF-a was added after inhibition of PKC by H7, apoptosis was observed, and the activation of nuclear factor kappa B (NF-κB) was also observed. After the inhibition of protein kinase B (Akt) by the LY294002 and p38 mitogen-activqated protein kinase (p38MAPK) by SB203580, the addition of TNF-α did not cause apoptosis. However, after the inhibition of MAPK/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) with U0120, apoptosis was observed when TNF-α was added. In the western blotting anlysis, phosphorylation of MEK1/2 at 60 minutes after the addition of TNF-α. However, it was noted that after pretreatment with H7, a significant decrease in phosphorylated MEK1/2 was observed. The findings of the present experiment suggest that MEK1/2 plays an important role in TNF-α-resistance in TNF-α-resistant B16 melanoma BL6 cells. Furthermore, it was revealed that MEK1/2 was more important than NF-κB, Akt and p38 in anti-apoptotic PKC signaling and that TNF-a-resistance can be overcome by inhibiting MEK1/2. These results suggest the possibility of development of a new anticancer drug treatment.

肿瘤坏死因子α（TNF-α）通过多种途径调节各种事件。许多肿瘤细胞对这种细胞因子具有抵抗力。用放线菌素D预处理这些细胞增强TNF-α诱导的凋亡。本研究探讨了蛋白激酶C（Protein kinase C，PKC）的抑制是否能诱导肿瘤细胞TNF-α耐药的凋亡及其机制。当H7抑制PKC后再加入TNF-α时，可观察到细胞凋亡，同时也观察到核因子κ B（NF-κB）的激活。在LY 294002和SB 203580分别抑制蛋白激酶B（Akt）和p38丝裂原活化蛋白激酶（p38 MAPK）后，加入TNF-α并不引起细胞凋亡。U 0120抑制MAPK/细胞外信号调节激酶1/2（MEK 1/2）后，加入TNF-α后，细胞凋亡明显。Western blotting分析发现，加入TNF-α后60 min，MEK 1/2磷酸化水平明显降低。然而，注意到在用H7预处理后，观察到磷酸化的MEK 1/2显著减少。本实验结果提示MEK 1/2在B16黑色素瘤BL 6细胞TNF-α抗性中起重要作用。此外，揭示了MEK 1/2在抗凋亡PKC信号传导中比NF-κB、Akt和p38更重要，并且可以通过抑制MEK 1/2来克服TNF-α抗性。这些结果提示了开发新的抗癌药物治疗的可能性。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diethyldithiocarbamate can induce two different type of death : apoposis and necrosis medating the differential MAP kinase activation and redox regulation in HL60 cells

二乙基二硫代氨基甲酸盐可诱导两种不同类型的死亡：凋亡和坏死，介导HL60细胞中不同的MAP激酶激活和氧化还原调节。

DOI：
发表时间：
2004
期刊：
Molecular and Cellular Biochemistry 265
影响因子：
0
作者：
Kunimatsu S;Tomidokoro A;Mishima K;Takamoto H;Tomita G;Iwase A;Araie M;Nishida et al.
通讯作者：
Nishida et al.

C-kinaseそがいによるTNFα壊死効果の増強機序

C-激酶刺激增强TNFα坏死作用的机制