Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways
Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways
复制标题
DOI：
10.1016/s0003-9861(02)00430-7
复制
发表时间：
2002-10-15
影响因子：
3.9
通讯作者：
Zhang, YD
中科院分区：
文献类型：
--
作者：
Liu, SL;Lin, X;Zhang, YD
活性氧（ROS）是细胞内信号传导机制的重要组成部分，它调节着许多细胞过程。锰超氧化物歧化酶（MnSOD）可通过改变细胞内活性氧水平来调节细胞生长。在我们的研究中，我们研究了活性氧对7721人肝癌细胞增殖的影响。用H2 O2（1-10 μ M）处理或转染反义MnSOD cDNA构建体显著增加细胞增殖。近年来，有丝分裂原活化蛋白激酶（MAPK）和蛋白激酶B（PKB）被认为与细胞生长有关。因此，我们评估了ROS激活MAPK和PKB的能力。10 μ M H_2O_2能迅速和短暂地激活PKB和细胞外信号调节激酶（ERK），而p38 MAPK和JNK活性无明显变化。ROS诱导的PKB激活被磷脂酰肌醇3-激酶（PI 3-K）抑制剂LY 294002所阻断，表明PI 3-K是7721细胞中PKB激活的上游介质。正义PKB cDNA转染7721细胞可促进c-fos和c-jun的表达，提示ROS可能通过PKB途径调节c-fos和c-jun的表达。此外，我们发现外源性H_2O_2可刺激转染反义PKB cDNA的PKB-AS 7721细胞的增殖，这部分依赖于JNK的激活，提示H_2O_2通过PI_3-K/PKB和JNK -信号通路之间的相互作用促进肝癌细胞的增殖。胰岛素可刺激7721细胞增殖，但不依赖于PI 3-K/PKB和JNK通路的相互作用。此外，H2 O2对正常肝细胞中PI 3-K/PKB和JNK信号通路无明显影响。综上所述，我们发现ROS通过特定的信号通路（PI 3-K/PKB和JNK通路之间的相互作用）调控肝癌细胞的生长，这可能为阐明肝癌的发生机制提供了新的线索。(C)2002 Elsevier Science（美国）。All rights reserved.
Reactive oxygen species (ROS) are important for intracellular signaling mechanisms regulating many cellular processes. Manganese superoxide dismutase (MnSOD) may regulate cell growth by changing the level of intracellular ROS. In our study, we investigated the effect of ROS on 7721 human hepatoma cell proliferation. Treatment with H2O2 (1-10 muM) or transfection with antisense MnSOD cDNA constructs significantly increased the cell proliferation. Recently, the mitogen-activated protein kinases (MAPK) and the protein kinase B (PKB) were proposed to be involved in cell growth. Accordingly, we assessed the ability of ROS to activate MAPK and PKB. PKB and extracellular signal-regulated kinase (ERK) were both rapidly and transiently activated by 10 muM H2O2, but the activities of p38 MAPK and JNK were not changed. ROS-induced PKB activation was abrogated by the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002, suggesting that PI3-K is an upstream mediator of PKB activation in 7721 cells. Transfection with sense PKB cDNA promoted c-fos and c-jun expression in 7721 cells, suggesting that ROS may regulate c-fos and c-jun expression via the PKB pathway. Furthermore we found that exogenous H2O2 could stimulate the proliferation of PKB-AS7721 cells transfected with antisense PKB cDNA, which was partly dependent on JNK activation, suggesting that H2O2 stimulated hepatoma cell proliferation via cross-talk between the PI3-K/PKB and the JNK - signaling pathways. However, insulin could stimulate 7721 cell proliferation, which is independent of cross-talk between PI3-K/PKB and JNK pathways. In addition, H2O2 did not induce the cross-talk between the PI3-K/PKB and the JNK pathways in normal liver cells. Taken together, we found that ROS regulate hepatoma cell growth via specific signaling pathways (cross-talk between PI3-K/PKB and JNK pathway) which may provide a novel clue to elucidate the mechanism of hepatoma carcinogenesis. (C) 2002 Elsevier Science (USA). All rights reserved.