ATF4在肿瘤中的研究进展
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摘要
肿瘤的发生和发展是一个多因素、多步骤和多基因参与的过程,其中不仅仅涉及肿瘤本身,低氧、低葡萄糖、低氨基酸、低p H值的肿瘤微环境与肿瘤相互作用,导致应激反应如:缺氧诱导因子(HIFs)、未折叠蛋白反应(UPR)和腺苷酸活化蛋白激酶反应途径(AMPK)以维持肿瘤代谢平衡,参与肿瘤进展的血管生成、浸润、转移及治疗抵抗发生。ATF4是活化转录因子(ATF)家族代指一大组的基本区域亮氨酸拉链(b ZIP)转录因子成员之一,是调控促生存基因的转录因子,在正常组织的生长发育中起重要作用,能够调控多种相关基因的合成,参与自噬,氧化还原反应和细胞凋亡,近年来研究发现与正常组织相比,ATF4在多种肿瘤组织中表达升高,特别是在肿瘤组织乏营养区域即肿瘤微环境,提示在肿瘤微环境中ATF4参与维持肿瘤代谢平衡,使肿瘤细胞在乏营养下存活,和肿瘤的进展、多种抗肿瘤药物治疗耐药的发生相关,本文主要从ATF4的来源,在生长和发育中的作用,在肿瘤生物学中的作用,在肿瘤进展和药物耐药方面的作用机制作一综述,并对目前有一些以ATF4为相关靶点的抗肿瘤治疗研究方向及正在开发的药物作一探讨,为以ATF4为靶点的相关抗肿瘤研究提供研究思路。
The occurrence and development of carcinoma depend on a number of factors and multiple genetic changes and is a multi-step process. Besides cancer tissue itself,the hypoxia,low glucose,low amino acids and low PH value of the cancer microenvironments were also interacted with cancer,these cancer microenvironments resulted in stress response,including stabilization of hypoxia-inducible factors( HIFs),induction of the unfolded protein response( UPR) and activation of the AMP-activated protein kinase( AMPK) pathway,which was also involved in cancer progression,angiogenesis,invasion,metastasis and therapeutic resistance. Activating transcription factor 4( ATF4) belongs to the activator of transcription family( ATF) with the basic region leucine zipper( b ZIP) that is involved in protein-protein interactions.ATF4 plays important role in regulating the survival,growth and development of normal tissue,and involved in autophagy,redox and apoptosis. The recent study shows that the expression of ATF4 increase in various cancer tissues,especially in cancer microenvironment( region lacking of nutrients),suggesting that ATF4 in cancer microenvironment is involved in the maintenance of cancer metabolism,the survival of cancer cell in the lack of nutrition,and is related with cancer progression and drugs resistance. This paper mainly summarizes about the sources and role of ATF4 in cancer cell growth and development and in cancer biology,and its mechanism in cancer progression and drug resistance,the paper also prospects the role of ATF4 related cancer treatment,and provide ideas for anti-cancer research targeting the ATF4 pathway.
The occurrence and development of carcinoma depend on a number of factors and multiple genetic changes and is a multi-step process. Besides cancer tissue itself,the hypoxia,low glucose,low amino acids and low PH value of the cancer microenvironments were also interacted with cancer,these cancer microenvironments resulted in stress response,including stabilization of hypoxia-inducible factors( HIFs),induction of the unfolded protein response( UPR) and activation of the AMP-activated protein kinase( AMPK) pathway,which was also involved in cancer progression,angiogenesis,invasion,metastasis and therapeutic resistance. Activating transcription factor 4( ATF4) belongs to the activator of transcription family( ATF) with the basic region leucine zipper( b ZIP) that is involved in protein-protein interactions.ATF4 plays important role in regulating the survival,growth and development of normal tissue,and involved in autophagy,redox and apoptosis. The recent study shows that the expression of ATF4 increase in various cancer tissues,especially in cancer microenvironment( region lacking of nutrients),suggesting that ATF4 in cancer microenvironment is involved in the maintenance of cancer metabolism,the survival of cancer cell in the lack of nutrition,and is related with cancer progression and drugs resistance. This paper mainly summarizes about the sources and role of ATF4 in cancer cell growth and development and in cancer biology,and its mechanism in cancer progression and drug resistance,the paper also prospects the role of ATF4 related cancer treatment,and provide ideas for anti-cancer research targeting the ATF4 pathway.
引文
[1]Anindya R.Non-heme dioxygenases in tumor hypoxia:They’re all bound with the same fate[J].DNA Repair(Amst),2016,48(12):27-36.
[2]Li X,Yu X,Dai D,et al.The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters[J].Oncotarget,2016,7(17):23141-23155.
[3]Ananieva E.Targeting amino acid metabolism in cancer growth and antitumor immune response[J].World J Biol Chem,2015,6(4):281-289.
[4]Shmeeda H,Amitay Y,Tzemach D,et al.Liposome encapsulation of zoledronic acid results in major changes in tissue distribution and increase in toxicity[J].J Control Release,2013,167(3):265-275.
[5]Sano R,Reed JC.ER stress-induced cell death mechanisms[J].Biochim Biophys Acta,2013,1833(12):3460-3470.
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[9]Wei N,Zhu LQ,Liu D.ATF4:a Novel Potential Therapeutic Target for Alzheimer’s Disease[J].Mol Neurobiol,2015,52(3):1765-1770.
[10]Taniuchi S,Miyake M,Tsugawa K,et al.Integrated stress response of vertebrates is regulated by four e IF2αkinases[J].Sci Rep,2016,26(6):32886.
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[12]Bruhat A,Jousse C,Carraro V,et al.Activation of the e IF2α-ATF4pathway:an adaptative response to cellular stress[J].Med Sci(Paris),2015,31(12):1057-1060.
[13]Huggins CJ,Mayekar MK,Martin N,et al.C/EBPγis a critical regulator of cellular stress response networks through heterodimerization with ATF4[J].Mol Cell Biol,2015,36(5):693-713.
[14]Suragani RN,Zachariah RS,Velazquez JG,et al.Heme-regulated e IF2αkinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis[J].Blood,2012,119(22):5276-5284.
[15]Zhao Y,Zhou J,Liu D,et al.ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver[J].Blood,2015,126(21):2383-2391.
[16]Wang X,Wang G,Kunte M,et al.Modulation of angiogenesis by genetic manipulation of ATF4 in mouse model of oxygen-induced retinopathy[J].Invest Ophthalmol Vis Sci,2013,54(9):5995-6002.
[17]Danciu TE,Li Y,Koh A,et al.The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts[J].J Cell Biochem,2012,113(1):70-79.
[18]Brüning A,Rahmeh M,Friese K.Nelfinavir and bortezomib inhibit m TOR activity via ATF4-mediated sestrin-2 regulation[J].Mol Oncol,2013,7(6):1012-1018.
[19]Rozpedek W,Pytel D,Mucha B,et al.The Role of the PERK/e IF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress[J].Curr Mol Med,2016,16(6):533-544.
[20]Pettersen EO,Ebbesen P,Gieling RG,et al.Targeting tumour hypoxia to prevent cancer metastasis.From biology,biosensing and technology to drug development:the METOXIA consortium[J].J Enzyme Inhib Med Chem,2015,30(5):689-721.
[21]Tang X,Lucas JE,Chen JL,et al.Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs[J].Cancer Res,2012,72(2):491-502.
[22]Kim J,Yun M,Kim EO,et al.Generation of ROS by Decursin selectively induces the ER stress pathway components ATF4/PERK leading to the synergistic enhancement of TRAIL-induced apoptosis[J].Br J Pharmacol,2015,22(7):1085-1091.
[23]Ye J,Mancuso A,Tong X,et al.Pyruvate kinase M2 promotes de novo serine synthesis to sustain m TORC1 activity and cell proliferation[J].Proc Natl Acad Sci USA,2012,109(18):6904-6909.
[24]Kang MJ,Vasudevan D,Kang K,et al.4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging[J].J Cell Biol,2017,216(1):115-129.
[25]Wang Y,Ning Y,Alam GN,et al.Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway[J].Neoplasia,2013,15(8):989-997.
[26]Rzymski T,Petry A,Kraˇcun D,et al.The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress[J].Oncogene,2012,31(31):3621-3634.
[27]Horiguchi M,Koyanagi S,Okamoto A,et al.Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors[J].Cancer Res,2012,72(2):395-401.
[28]Tang X,Lucas JE,Chen JL,et al.Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs[J].Cancer Res,2012,72(2):491-502.
[29]Guan BJ,Krokowski D,Majumder M,et al.Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor e IF2α[J].J Biol Chem,2014,289(18):12593-12611.
[30]Zhang Z,Yin J,Zhang C,et al.Activating transcription factor 4 increases chemotherapeutics resistance of human hepatocellular carcinoma[J].Cancer Biol Ther,2012,13(6):435-442.
[31]Hu J,Dang N,Menu E,et al.Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition[J].Blood,2012,119(3):826-837.
[32]Notte A,Rebucci M,Fransolet M,et al.Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia:ATF4 activation regulates autophagy and inhibits apoptosis[J].Int J Biochem Cell Biol,2015,62(3):1-14.
[33]Wang S,Chen XA,Hu J,et al.ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells[J].Mol Cancer Ther,2015,14(4):877-888.
[34]Fan CF,Mao XY,Wang EH.Elevated p-CREB-2(ser 245)expression is potentially associated with carcinogenesis and development of breast carcinoma[J].Mol Med Report,2012,5(2):357-362.
[35]Bagheri-Yarmand R,Williams MD,Grubbs EG,et al.ATF4 Targets RET for Degradation and is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer[J].J Clin Endocrinol Metab,2016,102(1):449-499.
[2]Li X,Yu X,Dai D,et al.The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters[J].Oncotarget,2016,7(17):23141-23155.
[3]Ananieva E.Targeting amino acid metabolism in cancer growth and antitumor immune response[J].World J Biol Chem,2015,6(4):281-289.
[4]Shmeeda H,Amitay Y,Tzemach D,et al.Liposome encapsulation of zoledronic acid results in major changes in tissue distribution and increase in toxicity[J].J Control Release,2013,167(3):265-275.
[5]Sano R,Reed JC.ER stress-induced cell death mechanisms[J].Biochim Biophys Acta,2013,1833(12):3460-3470.
[6]林浩,郭君宾,刘泰然,等.内质网应激相关抗肿瘤治疗研究进展[J].中华全科医学,2015,13(11):1841-1843.
[7]Li DW,Dong P,Wang F,et al.Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1α[J].Asian Pac J Cancer Prev,2013,14(8):4853-4858.
[8]秦承东,任正刚,汤钊猷.缺氧微环境在肿瘤进展中的作用[J].肿瘤,2016,36(1):96-102.
[9]Wei N,Zhu LQ,Liu D.ATF4:a Novel Potential Therapeutic Target for Alzheimer’s Disease[J].Mol Neurobiol,2015,52(3):1765-1770.
[10]Taniuchi S,Miyake M,Tsugawa K,et al.Integrated stress response of vertebrates is regulated by four e IF2αkinases[J].Sci Rep,2016,26(6):32886.
[11]Jennings MD,Pavitt GD.A new function and complexity for protein translation initiation factor e IF2B[J].Cell Cycle,2014,13(17):2660-2665.
[12]Bruhat A,Jousse C,Carraro V,et al.Activation of the e IF2α-ATF4pathway:an adaptative response to cellular stress[J].Med Sci(Paris),2015,31(12):1057-1060.
[13]Huggins CJ,Mayekar MK,Martin N,et al.C/EBPγis a critical regulator of cellular stress response networks through heterodimerization with ATF4[J].Mol Cell Biol,2015,36(5):693-713.
[14]Suragani RN,Zachariah RS,Velazquez JG,et al.Heme-regulated e IF2αkinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis[J].Blood,2012,119(22):5276-5284.
[15]Zhao Y,Zhou J,Liu D,et al.ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver[J].Blood,2015,126(21):2383-2391.
[16]Wang X,Wang G,Kunte M,et al.Modulation of angiogenesis by genetic manipulation of ATF4 in mouse model of oxygen-induced retinopathy[J].Invest Ophthalmol Vis Sci,2013,54(9):5995-6002.
[17]Danciu TE,Li Y,Koh A,et al.The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts[J].J Cell Biochem,2012,113(1):70-79.
[18]Brüning A,Rahmeh M,Friese K.Nelfinavir and bortezomib inhibit m TOR activity via ATF4-mediated sestrin-2 regulation[J].Mol Oncol,2013,7(6):1012-1018.
[19]Rozpedek W,Pytel D,Mucha B,et al.The Role of the PERK/e IF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress[J].Curr Mol Med,2016,16(6):533-544.
[20]Pettersen EO,Ebbesen P,Gieling RG,et al.Targeting tumour hypoxia to prevent cancer metastasis.From biology,biosensing and technology to drug development:the METOXIA consortium[J].J Enzyme Inhib Med Chem,2015,30(5):689-721.
[21]Tang X,Lucas JE,Chen JL,et al.Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs[J].Cancer Res,2012,72(2):491-502.
[22]Kim J,Yun M,Kim EO,et al.Generation of ROS by Decursin selectively induces the ER stress pathway components ATF4/PERK leading to the synergistic enhancement of TRAIL-induced apoptosis[J].Br J Pharmacol,2015,22(7):1085-1091.
[23]Ye J,Mancuso A,Tong X,et al.Pyruvate kinase M2 promotes de novo serine synthesis to sustain m TORC1 activity and cell proliferation[J].Proc Natl Acad Sci USA,2012,109(18):6904-6909.
[24]Kang MJ,Vasudevan D,Kang K,et al.4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging[J].J Cell Biol,2017,216(1):115-129.
[25]Wang Y,Ning Y,Alam GN,et al.Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway[J].Neoplasia,2013,15(8):989-997.
[26]Rzymski T,Petry A,Kraˇcun D,et al.The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress[J].Oncogene,2012,31(31):3621-3634.
[27]Horiguchi M,Koyanagi S,Okamoto A,et al.Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors[J].Cancer Res,2012,72(2):395-401.
[28]Tang X,Lucas JE,Chen JL,et al.Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs[J].Cancer Res,2012,72(2):491-502.
[29]Guan BJ,Krokowski D,Majumder M,et al.Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor e IF2α[J].J Biol Chem,2014,289(18):12593-12611.
[30]Zhang Z,Yin J,Zhang C,et al.Activating transcription factor 4 increases chemotherapeutics resistance of human hepatocellular carcinoma[J].Cancer Biol Ther,2012,13(6):435-442.
[31]Hu J,Dang N,Menu E,et al.Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition[J].Blood,2012,119(3):826-837.
[32]Notte A,Rebucci M,Fransolet M,et al.Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia:ATF4 activation regulates autophagy and inhibits apoptosis[J].Int J Biochem Cell Biol,2015,62(3):1-14.
[33]Wang S,Chen XA,Hu J,et al.ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells[J].Mol Cancer Ther,2015,14(4):877-888.
[34]Fan CF,Mao XY,Wang EH.Elevated p-CREB-2(ser 245)expression is potentially associated with carcinogenesis and development of breast carcinoma[J].Mol Med Report,2012,5(2):357-362.
[35]Bagheri-Yarmand R,Williams MD,Grubbs EG,et al.ATF4 Targets RET for Degradation and is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer[J].J Clin Endocrinol Metab,2016,102(1):449-499.