氧化还原环境对肝癌细胞生长信号通路串话的调控作用研究
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摘要
正常的细胞生理代谢不可避免地产生活性氧分子(ROS),过量的ROS具有化学毒性并对生物大分子产生氧化损伤,从而导致细胞功能的紊乱、病变甚至癌变。细胞通过各种酶系和生物抗氧化剂清除细胞内过多的ROS,调整细胞内的氧化还原状态;但另一方面,ROS又是细胞信号转导系统的组成部分,许多信号传递分子的功能因氧还状态的改变而受调控。肿瘤细胞与正常细胞相比,具有增殖失控和凋亡受抑等特点,在其中起调控作用的信号转导途径会发生某些特异性变化。本课题以HepG2肝癌细胞为主要研究对象,利用内、外源性抗氧化剂/酶及活性氧的介入调节细胞内氧化还原状态以及各种蛋白特异性抑制剂的作用,采用基因转染、RT-PCR、Western blot、流式细胞仪、荧光标记等技术研究了HepG2内ROS主要来源、GSH水平的变化和ROS介导HepG2细胞增殖、凋亡相关信号转导通路蛋白、基因表达、信号通路串话的调控作用。
在预实验中采用电子传递链复合酶Ⅰ抑制剂鱼藤酮和NADPH氧化酶抑制剂DPI作用细胞,流式细胞仪和荧光成像等方法检测,表明HepG2细胞内的ROS主要来源于NADPH氧化酶,线粒体也是一个重要的源头;另一方面,对Chang细胞和HepG2细胞中及外源性干预HepG2氧还状态后GSH测定表明,HepG2细胞中的GSH比Chang细胞高,NADPH氧化酶抑制剂作用后,HepG2细胞的GSH水平升高,在这些过程中G6PD起着重要的作用;同时,预实验结果也表明,转染反义MnSOD cDNA和低浓度H_2O_2作用可以上调HepG2胞内的ROS,通过调节PI3K/Akt,MAPK相应蛋白的激活,促进转录因子AP-1,NF-κB mRNA的表达,从而调节HepG2细胞的增殖;转染正义MnSOD cDNA和抗氧化剂桑黄多糖干预则可以通过下调ROS而抑制HepG2的增殖。
课题在预实验的基础上,主要利用各种信号通路的抑制剂干预和JNK基因转染细胞发现:低浓度的H_2O_2应激细胞,同时促进Akt、ERK、PKCζ的激活,而JNK只有在Akt受到抑制的条件下才被激活,引起PI3K/Akt和JNK信号通路串话,共同参与HepG2细胞的增殖过程,但ERK、PKCζ却不参与该信号通路串话;对不同ROS来源途径进行干预发现调控Akt和PKCζ表达的ROS主要来源于NADPH氧化酶,而调控JNK蛋白表达的ROS主要来源于线粒体;各种抑制剂单独或联合预处理细胞时对HepG2细胞的增殖和程序性死亡产生了不同的影响。20μM的LY294002与15μM的SP600125预处理细胞后HepG2细胞Akt与JNK的激活被完全阻断,但HepG2细胞没有被完全抑制生长。
Normal cell metabolism inevitably produce the reactive oxygen species(ROS), excessive amount of ROS is chemical toxicity and can cause oxidative damage to the biological macromolecules, resulting in cell function disorders, diseases and even cancer .But cells can eliminate the excess ROS through a variety of bio-enzymes and antioxidant to adjust the redox state . However, on the other hand, ROS is an important component in the cell signal transduction system. Many of the protein in signaling transduction are activated because of the fluctuation of intracellular ROS. Tumor cells have the characteristics of sustained proliferation and evading apoptosis compared with normal cells since their regulation of the signal transduction pathway could happen some specific changes. HepG2 cell line was selected as the main study object. The involvement of exogenous antioxidants / enzyme and low concentration H_2O_2 were used to regulate the redox state and a variety of specific inhibitors of protein, gene transfection, RT - PCR, Western blot, flow cytometry, fluorescence techniques were used to study the major source of intracellular ROS, the change of GSH level and the signaling pathway protein、gene expression、the possible cross talking of the signaling pathway that involved in the proliferation and apoptosis of HepG2 cells.
In the pre-experiment The inhibitor of electron transport chain complex enzymeI rotenone and NADPH oxidase inhibitor DPI were used to pretreat the cells andflow cytometry and fluorescence imaging were used to detect the concentration of ROS. Result shows that the intracellular ROS of HepG2 mainly comes from the NADPH oxidase and Mitochondria is also an important source. On the other hand, the determination of GSH level of Chang cells、HepG2 cells and exogenous intervention of HepG2 redox state show that HepG2 cells have higher GSH level than Chang cells. After the pretreatment with inhibitor of NADPH oxidase ,the GSH level increased and G6PD plays an important role during the procedure. At the same time, pre-test result also shows that down-regulation of MnSOD expression by transfection of antisense MnSOD construct and exogenous low concentration H_2O_2 can elevate the intracellular ROS and regulate HepG2 cells proliferation by induce the Phosphorylation of Akt and relative MAPK protein, following enhanced transcription factor AP-1 and NF-κB expression. However, antioxidant Phellinus Igniarius Extract(PIE) and over-expression of MnSOD can downregulate the intracellular ROS ,which cause to the inhibition of HepG2 cell growth.
On the basis of pre-experiments, we used the methods of gene transfection and signaling pathway inhibitors to interfere with cells, we found that when low concentrations of H_2O_2 was used to treat cells ,the Akt、ERK and PKCζwere activated and JNK was only activated in the condition of suppression of Akt, cause PI3K/Akt and JNK signaling pathway crosstalk, to participate proliferation process of HepG2 cells, but ERK, PKCζwere not involved in that signaling pathway crosstalk; Intervening different sources of ROS found that ROS regulated the expression of Akt PKCζmainly comes from NADPH oxidase, while ROS regulated the expression JNK mainly comes from the mitochondria; Various inhibitors alone or combination pretreatment cells have different impact on proliferation and programmed death of HepG2 cells. When used 20μM of LY294002 and 15μM's SP600125 to pretreat HepG2 cells the activation of Akt and JNK were completely blocked, But the growth of HepG2 cells were not completely inhibited .
在预实验中采用电子传递链复合酶Ⅰ抑制剂鱼藤酮和NADPH氧化酶抑制剂DPI作用细胞,流式细胞仪和荧光成像等方法检测,表明HepG2细胞内的ROS主要来源于NADPH氧化酶,线粒体也是一个重要的源头;另一方面,对Chang细胞和HepG2细胞中及外源性干预HepG2氧还状态后GSH测定表明,HepG2细胞中的GSH比Chang细胞高,NADPH氧化酶抑制剂作用后,HepG2细胞的GSH水平升高,在这些过程中G6PD起着重要的作用;同时,预实验结果也表明,转染反义MnSOD cDNA和低浓度H_2O_2作用可以上调HepG2胞内的ROS,通过调节PI3K/Akt,MAPK相应蛋白的激活,促进转录因子AP-1,NF-κB mRNA的表达,从而调节HepG2细胞的增殖;转染正义MnSOD cDNA和抗氧化剂桑黄多糖干预则可以通过下调ROS而抑制HepG2的增殖。
课题在预实验的基础上,主要利用各种信号通路的抑制剂干预和JNK基因转染细胞发现:低浓度的H_2O_2应激细胞,同时促进Akt、ERK、PKCζ的激活,而JNK只有在Akt受到抑制的条件下才被激活,引起PI3K/Akt和JNK信号通路串话,共同参与HepG2细胞的增殖过程,但ERK、PKCζ却不参与该信号通路串话;对不同ROS来源途径进行干预发现调控Akt和PKCζ表达的ROS主要来源于NADPH氧化酶,而调控JNK蛋白表达的ROS主要来源于线粒体;各种抑制剂单独或联合预处理细胞时对HepG2细胞的增殖和程序性死亡产生了不同的影响。20μM的LY294002与15μM的SP600125预处理细胞后HepG2细胞Akt与JNK的激活被完全阻断,但HepG2细胞没有被完全抑制生长。
Normal cell metabolism inevitably produce the reactive oxygen species(ROS), excessive amount of ROS is chemical toxicity and can cause oxidative damage to the biological macromolecules, resulting in cell function disorders, diseases and even cancer .But cells can eliminate the excess ROS through a variety of bio-enzymes and antioxidant to adjust the redox state . However, on the other hand, ROS is an important component in the cell signal transduction system. Many of the protein in signaling transduction are activated because of the fluctuation of intracellular ROS. Tumor cells have the characteristics of sustained proliferation and evading apoptosis compared with normal cells since their regulation of the signal transduction pathway could happen some specific changes. HepG2 cell line was selected as the main study object. The involvement of exogenous antioxidants / enzyme and low concentration H_2O_2 were used to regulate the redox state and a variety of specific inhibitors of protein, gene transfection, RT - PCR, Western blot, flow cytometry, fluorescence techniques were used to study the major source of intracellular ROS, the change of GSH level and the signaling pathway protein、gene expression、the possible cross talking of the signaling pathway that involved in the proliferation and apoptosis of HepG2 cells.
In the pre-experiment The inhibitor of electron transport chain complex enzymeI rotenone and NADPH oxidase inhibitor DPI were used to pretreat the cells andflow cytometry and fluorescence imaging were used to detect the concentration of ROS. Result shows that the intracellular ROS of HepG2 mainly comes from the NADPH oxidase and Mitochondria is also an important source. On the other hand, the determination of GSH level of Chang cells、HepG2 cells and exogenous intervention of HepG2 redox state show that HepG2 cells have higher GSH level than Chang cells. After the pretreatment with inhibitor of NADPH oxidase ,the GSH level increased and G6PD plays an important role during the procedure. At the same time, pre-test result also shows that down-regulation of MnSOD expression by transfection of antisense MnSOD construct and exogenous low concentration H_2O_2 can elevate the intracellular ROS and regulate HepG2 cells proliferation by induce the Phosphorylation of Akt and relative MAPK protein, following enhanced transcription factor AP-1 and NF-κB expression. However, antioxidant Phellinus Igniarius Extract(PIE) and over-expression of MnSOD can downregulate the intracellular ROS ,which cause to the inhibition of HepG2 cell growth.
On the basis of pre-experiments, we used the methods of gene transfection and signaling pathway inhibitors to interfere with cells, we found that when low concentrations of H_2O_2 was used to treat cells ,the Akt、ERK and PKCζwere activated and JNK was only activated in the condition of suppression of Akt, cause PI3K/Akt and JNK signaling pathway crosstalk, to participate proliferation process of HepG2 cells, but ERK, PKCζwere not involved in that signaling pathway crosstalk; Intervening different sources of ROS found that ROS regulated the expression of Akt PKCζmainly comes from NADPH oxidase, while ROS regulated the expression JNK mainly comes from the mitochondria; Various inhibitors alone or combination pretreatment cells have different impact on proliferation and programmed death of HepG2 cells. When used 20μM of LY294002 and 15μM's SP600125 to pretreat HepG2 cells the activation of Akt and JNK were completely blocked, But the growth of HepG2 cells were not completely inhibited .
引文
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[1]Irani K.Oxidant signaling in vascular cell growth,death and survival.Circ.Res.2000,87,179-183
[2]Shi D.Y,Liu S.L,Redox stress regulates cell proliferation and apoptosis of human hepatoma through Akt protein phosphorylation.FEBS Letters,May,2003;542(1-3):60-64.
[3]Liu SL,Shi DY,Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways.Archives of Biochemistry and Biophysics,2002;406(2):173-182
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[1]SL Liu,DY Shi.Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways.Archives of Biochemistry and Biophysics,2002;406(2):173-182
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[1]Irani K.Oxidant signaling in vascular cell growth,death and survival.Circ.Res.2000,87,179-183
[2]Shi D.Y,Liu S.L,Redox stress regulates cell proliferation and apoptosis of human hepatoma through Akt protein phosphorylation.FEBS Letters,May,2003;542(1-3):60-64.
[3]Liu SL,Shi DY,Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways.Archives of Biochemistry and Biophysics,2002;406(2):173-182
[4]Nemeth I,Boda D,Blood glutathione redox ratio as a parameter of oxidative stress in premature infants with IRDS,Free radic boil reed.,1994,16(3):347-353
[5]Nvarro J,Obrador E,Pellicer JA,et al.,Blood gluthione as an index of radiation induced oxidative stress in mice and humans.Free radic boil med.,1997,22(7):1203-1209
[6]Bravi MC,Pietrangeli P,Laurenti O,et al.,Polyol pathway activity and gluthione redox status in non-insulin-dependent diabetic patients.Metabolism.,1997,46(10):1194-1198
[7]Zhu Q,Zhang WG,Wang LF,et al.,Resverator induced apoptosis and cell arrest in cancer cells,Journal of the fouth military medical university,2005,26(21):1935-1937
[8]Hao CY,Su HX,Wei HL,Resverator induces apoptosis in K526 cells through a Fas-dependent pathway,The practical journal of cancer,2004,19(6):561-566
[9]Wang JL,Zhao LX,Jing YK,Depletion of glutathione and the apoptosis of tumor cells,Chinese journal of medicinal chemistry,2003,13(6):361-366
[10]Hirose K,Longo DL,Oppenheim JJ,et al.Overexpression of mitochomdrial,manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin-1,tumor necrosis factor,selected anticancer drugs and ionizing radiation.FASEB J,1993,7:361-368
[11]金冬雁,梨孟枫译,分子克隆实验指南,第三版,科学出版社,2000,北京,PP786-810
[12]史峰,生物化学实验,浙江大学出版社,聚丙烯酰氨凝胶电泳,2002,57-82
[13]Cullen JJ,Mitros FA,Oberley LW.,Expression of antioxidant enzymes in diseases of the human pancreas:another link between chronic pancreatitis ans pancreatic cancer.Pancreas,2003,26(1):23-27
[14]Bostwick DG,Alexander EE,Singh R,et al.,Antioxidant enzyme expression and reactive oxygen species damage in preostatic intraepithelial neoplasia and cancer,Cancer,2000,89(1):123-134
[15]Kumaraguruparan R,Subapriya R,Viswanathan P,et al.,Tissue lipid peroxidation and antioxidant status in patients with adenocarcinoma of the breast,Clin chim acta,2002,325(1-2):165-170
[16]Kolanjiappan K,Ramachandran CR,Manoharan S.Biochemical changes in tumor tissues of oral cancer patients,Clin biochem,2003,36(1):61-65
[17]Pandolfi PP,Sonati F,Rivi R,et al.,Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase:G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress.EMBO J,1995,14:5209-5215
[18]Cheng AJ,Chiu DT,See LC,et al.,Poor prognosis in nasopharyngeal cancer p-atients with low glucose-6-phosphate dehydrogenase activity,Jpn.J.Cancer Res,2001,92(5):576-581
[1]SL Liu,DY Shi.Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways.Archives of Biochemistry and Biophysics,2002;406(2):173-182
[2]Vlahos,C.J.,et al.,A specific inhibitor of phosphatidylinositol 3-kinase 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002).J.Biol.Chem.1994,269,5241
[3]Bennett,B.L.,et al,SP600125,an anthrapyrazolone inhibitor of Jun N-terminal kinase.Proc.Natl.Acad.Sci.USA 98,2001,13681-13686
[4]Alessi,et al.,PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.J.Biol.Chem.1995,270,27489-27494
[5]Martindale JL,Holbrook NJ,Cellular response to oxidative stress:signaling for suicide and survival,J Cell Physiol,2002,192(1):1-15
[6]Vivanco I,Sawyer CL,The phosphatidylinositol 3-kinase Akt pathway in human cancer,Nat.Rev.Cancer,2002,2:489-501
[7]Roy HK,Olusola BF,Clemens DL,et al.,Akt proto-oncogene overexpression is an early event during sporadic colon carcinogenesis,Carcinogenesis,2002,23:201-205
[8] Ventura JJ,Cogswell P,Flavell RA,et al.,JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species,Genes Dev.,2004,18(23):2905-2915
[9] Lee SB,Hong SH,Kim H,et al.,Co-induction of cell death and survival pathways by phosphoinositide-3-kinase ,Life Sci.,2005,78(1):91-98
[10] Matsuzawa A, Ichijo H,Stress-responsive protein kinases in redox-regulated apoptosis signaling.Antioxid Redox Signal,2005,7(3-4):472-481
[11] Wang WH,Gregori G, Hullinger RL,er al.,Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor(TNF) receptor 1/TNF-αexpression, Mol Cell Biol.,2004,24(23): 10352-10365
[12] Marian V.,Dieter L.,Jan M.et al,Free radicals and antioxidants in normal physiological functions and human disease,The international journal of biochemistry & cell biology,2007,39:44-84