SIRT3在白血病耐药中作用的研究进展
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摘要
白血病是一类源自异常造血干/祖细胞的恶性克隆性疾病,解决其化学治疗中的耐药问题是白血病治疗的关键。SIRT3是主要的线粒体NAD+依赖性去乙酰化酶,可靶向调节多种代谢途径的酶和转录因子,在肿瘤中具有双重作用。在白血病细胞中活性氧簇(reactive oxygen species,ROS)水平和其耐药性紧密关联。SIRT3可通过多种途径降低ROS水平,增强肿瘤细胞对于氧化应激的应对能力,从而维持其生存。而在SIRT3去乙酰化酶活性降低时,这一作用减弱,使得肿瘤对于治疗药物更加敏感。通过研究SIRT3在白血病耐药中的作用,可能找到新的白血病治疗的靶点。该文综述了SIRT3在白血病耐药中作用的研究进展。
Leukemia is a clonal malignant disease originating from abnormal hematopoietic stem cells or progenitor cells. The key issue of leukemia treatment is its drug-resistance. SIRT3 is the main mitochondrial NAD+ dependent deacetylase. It regulates enzymes and transcription factors of many metabolism pathways. SIRT3 acts both as oncogenic gene and tumor-suppressing gene in the oncogenesis of different cancers. Studies have shown that reactive oxygen species(ROS) level is closely related to drug resistance of cancer cells. ROS level is elevated in leukemia cells, thus affecting its drug resistance. SIRT3 can downregulate ROS level in many ways and enhance cell survival in the case of oxidative stress. Decreased deacetylase activity of SIRT3 makes leukemic cells more vulnerable to oxidative stress so that they are more sensitive to current chemotherapies. Through discovering the function of SIRT3 in leukemia cells, a chance of finding a new target for leukemia treatment can be found. This article reviews recent advances on the role of SIRT3 in leukemia drug resistance.
Leukemia is a clonal malignant disease originating from abnormal hematopoietic stem cells or progenitor cells. The key issue of leukemia treatment is its drug-resistance. SIRT3 is the main mitochondrial NAD+ dependent deacetylase. It regulates enzymes and transcription factors of many metabolism pathways. SIRT3 acts both as oncogenic gene and tumor-suppressing gene in the oncogenesis of different cancers. Studies have shown that reactive oxygen species(ROS) level is closely related to drug resistance of cancer cells. ROS level is elevated in leukemia cells, thus affecting its drug resistance. SIRT3 can downregulate ROS level in many ways and enhance cell survival in the case of oxidative stress. Decreased deacetylase activity of SIRT3 makes leukemic cells more vulnerable to oxidative stress so that they are more sensitive to current chemotherapies. Through discovering the function of SIRT3 in leukemia cells, a chance of finding a new target for leukemia treatment can be found. This article reviews recent advances on the role of SIRT3 in leukemia drug resistance.
引文
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[26]Cheng Y,Dai C,Zhang J.SIRT3-SOD2-ROS pathway is involved in linaloolinduced glioma cell apoptotic death[J].Acta Biochim Pol,2017,64(2):343-350.
[27]Zhao XL,Yu CZ.Vosaroxin induces mitochondrial dysfunction and apoptosis in cervical cancer HeLa cells:involvement of AMPK/Sirt3/HIF-1 pathway[J].Chem Biol Interact,2018:57-63.
[28]Giralt A,Hondares E,Villena JA,et al.Peroxisome proliferator-activated receptor-γcoactivator-1αcontrols transcription of the Sirt3 gene,an essential component of the thermogenic brown adipocyte phenotype[J].J Biol Chem,2011,286:16958-16966.
[29]Geoghegan F,Buckland RJ,Rogers ET,et al.Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells[J].Oncotarget,2017,8(55):94711-94725.
[30]Tao NN,Zhou HZ,Tang H,et al.Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway[J].Oncotarget,2016,7(31):50117-50130.
[31]Torrensmas M,Hernándezlópez R,Oliver J,et al.Sirtuin3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer[J].J Cell Physiol,2018,233(8).DOI:10.1002/jcp.26443.
[32]Eun K,Ham SW,Kim H.Cancer stem cell heterogeneity:origin and new perspectives on CSC targeting[J].BMB Rep,2017,50(3):117-125.
[33]Xu B,Wang S,Li R,et al.Disulfiram/copper selectively eradicates AMLleukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNKand inhibition of NF-κB and Nrf2[J].Cell Death Dis,2017,8(5):e2797.
[34]Wang LJ,Lee YC,Huang CH,et al.Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axismediated TNF-αupregulation[J].Biochem Pharmacol,2018.DOI:10.1016/j.bcp.
[35]Mesbahi Y,Zekri A,Ghaffari SH,et al.Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide inacute myeloid leukemia cells:novel synergistic mechanism via the mediation of reactive oxygen species[J].Eur JPharmacol,2018,834:65-76.
[36]Kim IG,Kim JS,Lee JH,et al.Genistein decreases cellular redox potential,partially suppresses cell growth in HL60 leukemia cells and sensitizes cells toγ-radiation-induced cell death[J].Mol Med Rep,2014,10(6):2786-2792.
[37]Fang Y,Wang J,Xu L,et al.Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells[J].Oncotarget,2016,7(24):35692-35702.
[38]Wang J,Fang Y,Yan L,et al.Erythroleukemia cells acquire an alternative mitophagy capability[J].Sci Rep,2016,6:24641.
[39]Evangelisti C,Evangelisti C,Chiarini F,et al.Autophagy in acute leukemias:a double-edged sword with important therapeutic implications[J].Biochim Biophys Acta,2015,1853(1):14-26.
[2]Zeichner SB,Gleason S,Antun AG,et al.Survival of patients diagnosed with primary refractory and relapsed acute myeloid leukemia from 2008-2012:a single institution experience[J].Blood,2015,126:4955.
[3]Kobayashi M,Takeda K,Narita T,et al.Mitochondrial intermediate peptidase is a novel regulator of sirtuin-3 activation by caloric restriction[J].Febs Letters,2017,591(24):4067-4073.
[4]Nguyen GTT,Schaefer S,Gertz M,et al.Structures of human sirtuin 3complexes with ADP-ribose and with carba-NAD+and SRT1720:binding details and inhibition mechanism[J].Acta Crystallogr D Biol Crystallogr,2013,69(8):1423-1432.
[5]Scher MB,Vaquero A,Reinberg D.SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress[J].Genes Dev,2007,21(8):920-928.
[6]Yu W,Dittenhafer KE,Denu JM.SIRT3 protein deacetylates isocitrate dehydrogenase 2(IDH2)and regulates mitochondrial redox status[J].J Biol Chem,2012,287(17):14078-14086.
[7]Zou X,Santa-Maria CA,O'Brien J,et al.Manganese superoxide dismutase acetylation and dysregulation,due to loss of SIRT3 activity,promote a luminal B-like breast carcinogenic-permissive phenotype[J].Antioxid Redox Signal,2016,25(6):326-336.
[8]Tseng AH,Shieh SS,Wang DL.SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage[J].Free Radic Biol Med,2013,63:222-234.
[9]Rangarajan P,Karthikeyan A,Lu J,et al.Sirtuin 3 regulates FOXO3a-mediated antioxidant pathway in microglia[J].Neuroscience,2015,311:398-414.
[10]Finley LWS,Haigis MC.Metabolic regulation by SIRT3:implications for tumorigenesis[J].Trends Mol Med,2012,18(9):516-523.
[11]Elena SD,Rosa S,Eubanks JH.The role of SIRT3 in the brain under physiological and pathological conditions[J].Front Cell Neurosci,2018,12:196.
[12]Desouki MM,Doubinskaia I,Gius D,et al.Decreased mitochondrial SIRT3expression is a potential molecular biomarker associated with poor outcome in breast cancer[J].Human Pathology,2014,45(5):1071-1077.
[13]Torrens MM,Pons DG,Sastre SJ,et al.SIRT3 silencing sensitizes breast cancer cells to cytotoxic treatments through an increment in ROS production[J].J Cell Biochem,2017,118(2):397-406.
[14]Liu C,Huang Z,Jiang H,et al.The sirtuin 3 expression profile is associated with pathological and clinical outcomes in colon cancer patients[J].Biomed Res Int,2014,2014(5795):871263.
[15]Cui Y,Qin L,Wu J,et al.SIRT3 enhances glycolysis and proliferation in SIRT3-expressing gastric cancer cells[J].PLoS One,2015,10(6):e0129834.
[16]George J,Nihal M,Singh CK,et al.Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma[J].J Invest Dermatol,2016,136(4):809-818.
[17]Choi J,Koh E,Lee YS,et al.Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma[J].Biochem Biophys Res Commun,2016,474(3):547-553.
[18]Liu Y,Liu YL,Cheng W,et al.The expression of SIRT3 in primary hepatocellular carcinoma and the mechanism of its tumor suppressing effects[J].Eur Rev Med Pharmacol Sci,2017,21(5):978-998.
[19]Wang JX,Yi Y,Li YW,et al.Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection[J].BMC Cancer,2014,14(1):297.
[20]Hyun JK,Liu P,Schumacker PT,et al.Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis[J].Immunity,2015,42(1):159-171.
[21]Dai G,Zheng D,Guo W,et al.Cinobufagin induces apoptosis in osteosarcoma cells via the mitochondria-mediated apoptotic pathway[J].Cell Physiol Biochem,2018,46(3):1134-1147.
[22]Hole PS,Zabkiewicz J,Munje CR,et al.Overproduction of NOX-derived ROSin AML promotes proliferation and is associated with defective oxidative stress signaling[J].Blood,2013,122(19):3322-3330.
[23]Lagadinou ED,Sach A,Callahan KP,et al.BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells[J].Cell Stem Cell,2013,12(3):329-341.
[24]Diehn M,Cho RW,Lobo N,et al.Association of reactive oxygen species levels and radioresistance in cancer stem cells[J].Nature,2009,458(7239):780-783.
[25]Bause AS,Haigis MC.SIRT3 regulation of mitochondrial oxidative stress[J].Exp Gerontol,2013,48(7):634-639.
[26]Cheng Y,Dai C,Zhang J.SIRT3-SOD2-ROS pathway is involved in linaloolinduced glioma cell apoptotic death[J].Acta Biochim Pol,2017,64(2):343-350.
[27]Zhao XL,Yu CZ.Vosaroxin induces mitochondrial dysfunction and apoptosis in cervical cancer HeLa cells:involvement of AMPK/Sirt3/HIF-1 pathway[J].Chem Biol Interact,2018:57-63.
[28]Giralt A,Hondares E,Villena JA,et al.Peroxisome proliferator-activated receptor-γcoactivator-1αcontrols transcription of the Sirt3 gene,an essential component of the thermogenic brown adipocyte phenotype[J].J Biol Chem,2011,286:16958-16966.
[29]Geoghegan F,Buckland RJ,Rogers ET,et al.Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells[J].Oncotarget,2017,8(55):94711-94725.
[30]Tao NN,Zhou HZ,Tang H,et al.Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway[J].Oncotarget,2016,7(31):50117-50130.
[31]Torrensmas M,Hernándezlópez R,Oliver J,et al.Sirtuin3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer[J].J Cell Physiol,2018,233(8).DOI:10.1002/jcp.26443.
[32]Eun K,Ham SW,Kim H.Cancer stem cell heterogeneity:origin and new perspectives on CSC targeting[J].BMB Rep,2017,50(3):117-125.
[33]Xu B,Wang S,Li R,et al.Disulfiram/copper selectively eradicates AMLleukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNKand inhibition of NF-κB and Nrf2[J].Cell Death Dis,2017,8(5):e2797.
[34]Wang LJ,Lee YC,Huang CH,et al.Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axismediated TNF-αupregulation[J].Biochem Pharmacol,2018.DOI:10.1016/j.bcp.
[35]Mesbahi Y,Zekri A,Ghaffari SH,et al.Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide inacute myeloid leukemia cells:novel synergistic mechanism via the mediation of reactive oxygen species[J].Eur JPharmacol,2018,834:65-76.
[36]Kim IG,Kim JS,Lee JH,et al.Genistein decreases cellular redox potential,partially suppresses cell growth in HL60 leukemia cells and sensitizes cells toγ-radiation-induced cell death[J].Mol Med Rep,2014,10(6):2786-2792.
[37]Fang Y,Wang J,Xu L,et al.Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells[J].Oncotarget,2016,7(24):35692-35702.
[38]Wang J,Fang Y,Yan L,et al.Erythroleukemia cells acquire an alternative mitophagy capability[J].Sci Rep,2016,6:24641.
[39]Evangelisti C,Evangelisti C,Chiarini F,et al.Autophagy in acute leukemias:a double-edged sword with important therapeutic implications[J].Biochim Biophys Acta,2015,1853(1):14-26.