靶向线粒体抑制肿瘤干细胞的研究进展
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摘要
一直以来肿瘤干细胞(cancer stem cells,CSCs)被认为是导致肿瘤发生、复发和转移的源头。研究显示,CSCs中线粒体结构形态的改变、信号通路的异常激活、线粒体功能紊乱、活性氧(reactive oxygen species,ROS)以及线粒体自噬等都是维持其干性、调控CSCs增殖和凋亡的关键,也是导致抗肿瘤治疗失败的主要原因之一。因此,本文就CSCs中线粒体在细胞凋亡、信号通路、能量代谢、ROS和线粒体自噬中的作用机制进行综述,以期为靶向CSCs中的线粒体进行抗肿瘤治疗提供有力的依据。
Cancer stem cells(CSCs) have long been considered as the origin of tumorigenesis, recurrence and metastasis. The changes of mitochondrial structure and morphology, abnormal activation of signaling pathways, mitochondrial dysfunction, reactive oxygen species(ROS) and mitochondrial autophagy in CSCs are the key factors to maintain the stem cell nature of CSCs and to regulate the proliferation and apoptosis of CSCs, and are also the major cause of anticancer treatment failure. This review particularly elucidates the mechanisms of mitochondria in CSCs affecting apoptosis, signaling pathway, energy metabolism, ROS and mitochondrial autophagy, in order to provide a powerful basis for the potential anti-tumor therapy targeting mitochondria in CSCs.
Cancer stem cells(CSCs) have long been considered as the origin of tumorigenesis, recurrence and metastasis. The changes of mitochondrial structure and morphology, abnormal activation of signaling pathways, mitochondrial dysfunction, reactive oxygen species(ROS) and mitochondrial autophagy in CSCs are the key factors to maintain the stem cell nature of CSCs and to regulate the proliferation and apoptosis of CSCs, and are also the major cause of anticancer treatment failure. This review particularly elucidates the mechanisms of mitochondria in CSCs affecting apoptosis, signaling pathway, energy metabolism, ROS and mitochondrial autophagy, in order to provide a powerful basis for the potential anti-tumor therapy targeting mitochondria in CSCs.
引文
[1]HEPPNER GH,MILLER BE.Tumor heterogeneity:biological implications and therapeutic consequences[J].Cancer Metastasis Rev,1983,2(1):5-23.
[2]LOUREIRO R,MESQUITA KA,MAGALHAES-NOVAIS S,et al.Mitochondrial biology in cancer stem cells[J].Semin Cancer Biol,2017,47:18-28.
[3]GHAFFARI S.Cancer,stem cells and cancer stem cells:old ideas,new developments[J].F1000 Med Rep,2011,3:23.
[4]CAMPBELL LL,POLYAK K.Breast tumor heterogeneity:cancer stem cells or clonal evolution?[J].Cell Cycle,2007,6(19):2332-2338.
[5]HEWITT HB.Studies of the dissemination and quantitative transplantation of a lymphocytic leukaemia of CBA mice[J].Br JCancer,1958,12(3):378-401.
[6]LAPIDOT T,SIRARD C,VORMOOR J,et al.A cell initiating human acute myeloid leukaemia after transplantation into SCIDmice[J].Nature,1994,367(6464):645-648.
[7]POLYAK K.Breast cancer:origins and evolution[J].J Clin Invest,2007,117(11):3155-3163.
[8]HERMAN PC,HUBER SL,HERRLER T,et al.Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer[J].Cell Stem Cell,2007,1(3):313-323.
[9]BERTOLINI G,ROZ L,PEREGO P,et al.Highly tumorigenic lung cancer CD133+cells display stem-like features and are spared by cisplatin treatment[J].Proc Natl Acad Sci USA,2009,106(38):16281-16286.
[10]WAND S,GARCIA AJ,WU M,et al.Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation[J].Proc Natl Acad Sci USA,2006,103(5):1480-1485.
[11]ZHANG S,BALCH C,CHAN MW,et al.Identification and characterization of ovarian cancer-initiating cells from primary human tumors[J].Cancer Res,2008,68(11):4311-4320.
[12]COX CV,EVELY RS,OAKHILL A,et al.Characterization of acute lymphoblastic leukemia progenitor cells[J].Blood,2004,104(9):2919-2925.
[13]SCHATTON T,MURPHY GF,FRANK NY,et al.Identification of cells initiating human melanomas[J].Nature,2008,451(7176):345-349.
[14]CLARKE MF,DICK JE,DIRKS PB,et al.Cancer stem cells-perspectives on current status and future directions:AACRWorkshop on cancer stem cells[J].Cancer Res,2006,66(19):9339-9344.
[15]SARKAR B,DOSCH J,SIMEONE DM.Cancer stem cells:a new theory regarding a timeless disease[J].Chem Rev,2009,109(7):3200-3208.
[16]KALKAVAN H,GREEN DR.MOMP,cell suicide as a BCL-2 family business[J].Cell Death Differ,2018,25(1):46-55.
[17]CHIPUK JE,BOUCHIER-HAYES L,GREENDR.Mitochondrial outer membrane permeabilization during apoptosis:the innocent bystander scenario[J].Cell Death Differ,2006,13(8):1396-1402.
[18]DUCHEN MR.Mitochondria in health and disease:perspectives on a new mitochondrial biology[J].Mol Aspects Med,2004,25(4):365-451.
[19]ODOUX C,FOHRER H,HOPPO T,et al.A stochastic model for cancer stem cell origin in metastatic colon cancer[J].Cancer Res,2008,68(17):6932-6941.
[20]KHATRA H,BOSE C,SINHA S.Discovery of hedgehog antagonists for cancer therapy[J].Curr Med Chem,2017,24(19):2033-2058.
[21]WU C,HU S,CHENG J,et al.Smoothened antagonist GDC-0449(Vismodegib)inhibits proliferation and triggers apoptosis in colon cancer cell lines[J].Exp Ther Med,2017,13(5):2529-2536.
[22]GU JW,RIZZO P,PANNUTI A,et al.Notch signals in the endothelium and cancer“stem-like”cells:opportunities for cancer therapy[J].Vasc Cell,2012,4:7.
[23]董亚萍,彭晓东,朴成钢.结肠癌干细胞:信号通路抑制剂与肿瘤耐药性[J].生命科学,2018,30(8):876-883.
[24]AKIYOSHI T,NAKAMURA M,YANAIK,et al.Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells[J].Gastroenterology,2008,134(1):131-144.
[25]ZHANG F,SUN H,ZHANG S,et al.Overexpression of PER3 inhibits selfrenewal capability and chemoresistance of colorectal cancer stem-like cells via inhibition of notch and beta-catenin signaling[J].Oncol Res,2017,25(5):709-719.
[26]MCKEAGE MJ,KOTASEK D,MARKMAN B,et al.PhaseⅠB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC[J].Target Oncol,2018,13(1):89-98.
[27]DUCHARTRE Y,KIM YM,KAHN M.The Wnt signaling pathway in cancer[J].Crit Rev Oncol Hematol,2016,99:141-149.
[28]姚彬,张庆华.Wnt/β-catenin信号通路在卵巢癌干细胞增殖、迁移和侵袭中的作用[J].中国组织工程研究,2018,22(25):4001-4006.
[29]MOON CM,KWON JH,KIM JS,et al.Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2(cyclooxygenase 2)and NOTCH/HES1 and activating PPARG in colorectal cancer[J].Int J Cancer,2014,134(3):519-529.
[30]TAI D,WELLS K,ARCAROLI J,et al.Targeting the Wnt signaling pathway in cancer therapeutics[J].Oncologist,2015,20(10):1189-1198.
[31]JIMENO A,GORDON M,CHUGH R,et al.A First-in-human phase I study of the anticancer stem cell agent ipafricept(OMP-54F28),a decoy receptor for wnt ligands,in patients with advanced solid tumors[J].Clin Cancer Res,2017,23(24):7490-7497.
[32]SANCHO P,BARNEDA D,HEESCHENC.Hallmarks of cancer stem cell metabolism[J].Br J Cancer,2016,114(12):1305-1312.
[33]PEIRIS-PAGES M,MARTINEZ-OUTSCHOORN UE,PESTELL RG,et al.Cancer stem cell metabolism[J].Breast Cancer Res,2016,18(1):55.
[34]CIAVARDELLI D,ROSSI C,BARCAROLID,et al.Breast cancer stem cells rely on fermentative glycolysis and are sensitive to2-deoxyglucose treatment[J].Cell Death Dis,2014,5:e1336.
[35]LIU PP,LIAO J,TANG ZJ,et al.Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway[J].Cell Death Differ,2014,21(1):124-135.
[36]GOGVADZE V,ORRENIUS S,ZHIVOTOVSKYB.Mitochondria in cancer cells:what is so special about them?[J].Trends Cell Biol,2008,18(4):165-173.
[37]MICHELAKIS ED,WEBSTER L,MACKEYJR.Dichloroacetate(DCA)as a potential metabolic-targeting therapy for cancer[J].Br J Cancer,2008,99(7):989-994.
[38]MICHELAKIS ED,SUTENDRA G,DROMPARIS P,et al.Metabolic modulation of glioblastoma with dichloroacetate[J].Sci Transl Med,2010,2(31):31-34.
[39]CARRACEDO A,CANTLEY LC,PANDOLFIPP.Cancer metabolism:fatty acid oxidation in the limelight[J].Nat Rev Cancer,2013,13(4):227-232.
[40]PRIGIONE A,FAULER B,LURZ R,et al.The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells[J].Stem Cells,2010,28(4):721-733.
[41]PASTO A,BELLIO C,PILOTTO G,et al.Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation,and resist glucose deprivation[J].Oncotarget,2014,5(12):4305-4319.
[42]SAMUDIO I,HARMANCEY R,FIEGL M,et al.Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction[J].J Clin Invest,2010,120(1):142-156.
[43]SANCHO P,BURGOS-RAMOS E,TAVERAA,et al.MYC/PGC-1αbalance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells[J].Cell Metab,2015,22(4):590-605.
[44]LI J,CONDELLO S,THOMES-PEPIN J,et al.Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells[J].Cell Stem Cell,2017,20(3):303-314.e5.
[45]MARYANOVICH M,GROSS A.A ROSrheostat for cell fate regulation[J].Trends Cell Biol,2013,23(3):129-134.
[46]JI Y,YANG C,TANG Z,et al.Corrigendum:adenylate kinase hCINAP determines selfrenewal of colorectal cancer stem cells by facilitating LDHA phosphorylation[J].Nat Commun,2017,8:16000.
[47]KRYSTON TB,GEORGIEV AB,PISSIS P,et al.Role of oxidative stress and DNA damage in human carcinogenesis[J].Mutat Res,2011,711(1/2):193-201.
[48]DIEHN M,CHO RW,LOBO NA,et al.Association of reactive oxygen species levels and radioresistance in cancer stem cells[J].Nature,2009,458(7239):780-783.
[49]ISHIMOTO T,NAGANO O,YAE T,et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-)and thereby promotes tumor growth[J].Cancer Cell,2011,19(3):387-400.
[50]KAWANO Y,IWAMA E,TSUCHIHASHI K,et al.CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer:A target for treatment[J].Lung Cancer,2017,113:72-78.
[51]MOLONEY JN,COTTER TG.ROS signalling in the biology of cancer[J].Semin Cell Dev Biol,2017,80:50-64.
[52]RUSSELL EG,GUO J,O’SULLIVAN EC,et al.7-Formyl-10-methylisoellipticine,a novel ellipticine derivative,induces mitochondrial reactive oxygen species(ROS)and shows anti-leukaemic activity in mice[J].Invest New Drugs,2016,34(1):15-23.
[53]LEBIEDZINSKA-ARCISZEWSKA M,OPARKAM,VEGA-NAREDO I,et al.The interplay between p66Shc,reactive oxygen species and cancer cell metabolism[J].Eur J Clin Invest,2015,45(Suppl 1):25-31.
[54]LEBIEDZINSKA M,KARKUCINSKA-WIECKOWSKA A,WOJTALA A,et al.Disrupted ATP synthase activity and mitochondrial hyperpolarisationdependent oxidative stress is associated with p66Shc phosphorylation in fibroblasts of NARP patients[J].Int J Biochem Cell Biol,2013,45(1):141-150.
[55]CUI J,GONG Z,SHEN HM.The role of autophagy in liver cancer:molecular mechanisms and potential therapeutic targets[J].Biochim Biophys Acta,2013,1836(1):15-26.
[56]LEI Y,ZHANG D,YU J,et al.Targeting autophagy in cancer stem cells as an anticancer therapy[J].Cancer Lett,2018,416:149.
[57]胡磊,戴海明.线粒体自噬的研究进展[J].中国细胞生物学学报,2018,40(4):594-601.
[58]YAN C,LUO L,GUO CY,et al.Doxorubicininduced mitophagy contributes to drug resistance in cancer stem cells from HCT8human colorectal cancer cells[J].Cancer Lett,2017,388:34-42.
[59]SONG YJ,ZHANG SS,GUO XL,et al.Autophagy contributes to the survival of CD133+liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment[J].Cancer Lett,2013,339(1):70-81.
[60]LI J,CHEN JN,ZENG TT,et al.CD133+liver cancer stem cells resist interferongamma-induced autophagy[J].BMCCancer,2016,16:15.
[61]YANG Y,FAN Y,QI Y,et al.Side population cells separated from A549 lung cancer cell line possess cancer stem cell-like properties and inhibition of autophagy potentiates the cytotoxic effect of cisplatin[J].Oncol Rep,2015,34(2):929-935.
[62]YANG MC,WANG HC,HOU YC,et al.Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine[J].Mol Cancer,2015,14:179.
[63]ZHENG YH,TIAN C,MENG Y,et al.Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells[J].J Cell Physiol,2012,227(1):127-135.
[2]LOUREIRO R,MESQUITA KA,MAGALHAES-NOVAIS S,et al.Mitochondrial biology in cancer stem cells[J].Semin Cancer Biol,2017,47:18-28.
[3]GHAFFARI S.Cancer,stem cells and cancer stem cells:old ideas,new developments[J].F1000 Med Rep,2011,3:23.
[4]CAMPBELL LL,POLYAK K.Breast tumor heterogeneity:cancer stem cells or clonal evolution?[J].Cell Cycle,2007,6(19):2332-2338.
[5]HEWITT HB.Studies of the dissemination and quantitative transplantation of a lymphocytic leukaemia of CBA mice[J].Br JCancer,1958,12(3):378-401.
[6]LAPIDOT T,SIRARD C,VORMOOR J,et al.A cell initiating human acute myeloid leukaemia after transplantation into SCIDmice[J].Nature,1994,367(6464):645-648.
[7]POLYAK K.Breast cancer:origins and evolution[J].J Clin Invest,2007,117(11):3155-3163.
[8]HERMAN PC,HUBER SL,HERRLER T,et al.Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer[J].Cell Stem Cell,2007,1(3):313-323.
[9]BERTOLINI G,ROZ L,PEREGO P,et al.Highly tumorigenic lung cancer CD133+cells display stem-like features and are spared by cisplatin treatment[J].Proc Natl Acad Sci USA,2009,106(38):16281-16286.
[10]WAND S,GARCIA AJ,WU M,et al.Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation[J].Proc Natl Acad Sci USA,2006,103(5):1480-1485.
[11]ZHANG S,BALCH C,CHAN MW,et al.Identification and characterization of ovarian cancer-initiating cells from primary human tumors[J].Cancer Res,2008,68(11):4311-4320.
[12]COX CV,EVELY RS,OAKHILL A,et al.Characterization of acute lymphoblastic leukemia progenitor cells[J].Blood,2004,104(9):2919-2925.
[13]SCHATTON T,MURPHY GF,FRANK NY,et al.Identification of cells initiating human melanomas[J].Nature,2008,451(7176):345-349.
[14]CLARKE MF,DICK JE,DIRKS PB,et al.Cancer stem cells-perspectives on current status and future directions:AACRWorkshop on cancer stem cells[J].Cancer Res,2006,66(19):9339-9344.
[15]SARKAR B,DOSCH J,SIMEONE DM.Cancer stem cells:a new theory regarding a timeless disease[J].Chem Rev,2009,109(7):3200-3208.
[16]KALKAVAN H,GREEN DR.MOMP,cell suicide as a BCL-2 family business[J].Cell Death Differ,2018,25(1):46-55.
[17]CHIPUK JE,BOUCHIER-HAYES L,GREENDR.Mitochondrial outer membrane permeabilization during apoptosis:the innocent bystander scenario[J].Cell Death Differ,2006,13(8):1396-1402.
[18]DUCHEN MR.Mitochondria in health and disease:perspectives on a new mitochondrial biology[J].Mol Aspects Med,2004,25(4):365-451.
[19]ODOUX C,FOHRER H,HOPPO T,et al.A stochastic model for cancer stem cell origin in metastatic colon cancer[J].Cancer Res,2008,68(17):6932-6941.
[20]KHATRA H,BOSE C,SINHA S.Discovery of hedgehog antagonists for cancer therapy[J].Curr Med Chem,2017,24(19):2033-2058.
[21]WU C,HU S,CHENG J,et al.Smoothened antagonist GDC-0449(Vismodegib)inhibits proliferation and triggers apoptosis in colon cancer cell lines[J].Exp Ther Med,2017,13(5):2529-2536.
[22]GU JW,RIZZO P,PANNUTI A,et al.Notch signals in the endothelium and cancer“stem-like”cells:opportunities for cancer therapy[J].Vasc Cell,2012,4:7.
[23]董亚萍,彭晓东,朴成钢.结肠癌干细胞:信号通路抑制剂与肿瘤耐药性[J].生命科学,2018,30(8):876-883.
[24]AKIYOSHI T,NAKAMURA M,YANAIK,et al.Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells[J].Gastroenterology,2008,134(1):131-144.
[25]ZHANG F,SUN H,ZHANG S,et al.Overexpression of PER3 inhibits selfrenewal capability and chemoresistance of colorectal cancer stem-like cells via inhibition of notch and beta-catenin signaling[J].Oncol Res,2017,25(5):709-719.
[26]MCKEAGE MJ,KOTASEK D,MARKMAN B,et al.PhaseⅠB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC[J].Target Oncol,2018,13(1):89-98.
[27]DUCHARTRE Y,KIM YM,KAHN M.The Wnt signaling pathway in cancer[J].Crit Rev Oncol Hematol,2016,99:141-149.
[28]姚彬,张庆华.Wnt/β-catenin信号通路在卵巢癌干细胞增殖、迁移和侵袭中的作用[J].中国组织工程研究,2018,22(25):4001-4006.
[29]MOON CM,KWON JH,KIM JS,et al.Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2(cyclooxygenase 2)and NOTCH/HES1 and activating PPARG in colorectal cancer[J].Int J Cancer,2014,134(3):519-529.
[30]TAI D,WELLS K,ARCAROLI J,et al.Targeting the Wnt signaling pathway in cancer therapeutics[J].Oncologist,2015,20(10):1189-1198.
[31]JIMENO A,GORDON M,CHUGH R,et al.A First-in-human phase I study of the anticancer stem cell agent ipafricept(OMP-54F28),a decoy receptor for wnt ligands,in patients with advanced solid tumors[J].Clin Cancer Res,2017,23(24):7490-7497.
[32]SANCHO P,BARNEDA D,HEESCHENC.Hallmarks of cancer stem cell metabolism[J].Br J Cancer,2016,114(12):1305-1312.
[33]PEIRIS-PAGES M,MARTINEZ-OUTSCHOORN UE,PESTELL RG,et al.Cancer stem cell metabolism[J].Breast Cancer Res,2016,18(1):55.
[34]CIAVARDELLI D,ROSSI C,BARCAROLID,et al.Breast cancer stem cells rely on fermentative glycolysis and are sensitive to2-deoxyglucose treatment[J].Cell Death Dis,2014,5:e1336.
[35]LIU PP,LIAO J,TANG ZJ,et al.Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway[J].Cell Death Differ,2014,21(1):124-135.
[36]GOGVADZE V,ORRENIUS S,ZHIVOTOVSKYB.Mitochondria in cancer cells:what is so special about them?[J].Trends Cell Biol,2008,18(4):165-173.
[37]MICHELAKIS ED,WEBSTER L,MACKEYJR.Dichloroacetate(DCA)as a potential metabolic-targeting therapy for cancer[J].Br J Cancer,2008,99(7):989-994.
[38]MICHELAKIS ED,SUTENDRA G,DROMPARIS P,et al.Metabolic modulation of glioblastoma with dichloroacetate[J].Sci Transl Med,2010,2(31):31-34.
[39]CARRACEDO A,CANTLEY LC,PANDOLFIPP.Cancer metabolism:fatty acid oxidation in the limelight[J].Nat Rev Cancer,2013,13(4):227-232.
[40]PRIGIONE A,FAULER B,LURZ R,et al.The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells[J].Stem Cells,2010,28(4):721-733.
[41]PASTO A,BELLIO C,PILOTTO G,et al.Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation,and resist glucose deprivation[J].Oncotarget,2014,5(12):4305-4319.
[42]SAMUDIO I,HARMANCEY R,FIEGL M,et al.Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction[J].J Clin Invest,2010,120(1):142-156.
[43]SANCHO P,BURGOS-RAMOS E,TAVERAA,et al.MYC/PGC-1αbalance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells[J].Cell Metab,2015,22(4):590-605.
[44]LI J,CONDELLO S,THOMES-PEPIN J,et al.Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells[J].Cell Stem Cell,2017,20(3):303-314.e5.
[45]MARYANOVICH M,GROSS A.A ROSrheostat for cell fate regulation[J].Trends Cell Biol,2013,23(3):129-134.
[46]JI Y,YANG C,TANG Z,et al.Corrigendum:adenylate kinase hCINAP determines selfrenewal of colorectal cancer stem cells by facilitating LDHA phosphorylation[J].Nat Commun,2017,8:16000.
[47]KRYSTON TB,GEORGIEV AB,PISSIS P,et al.Role of oxidative stress and DNA damage in human carcinogenesis[J].Mutat Res,2011,711(1/2):193-201.
[48]DIEHN M,CHO RW,LOBO NA,et al.Association of reactive oxygen species levels and radioresistance in cancer stem cells[J].Nature,2009,458(7239):780-783.
[49]ISHIMOTO T,NAGANO O,YAE T,et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-)and thereby promotes tumor growth[J].Cancer Cell,2011,19(3):387-400.
[50]KAWANO Y,IWAMA E,TSUCHIHASHI K,et al.CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer:A target for treatment[J].Lung Cancer,2017,113:72-78.
[51]MOLONEY JN,COTTER TG.ROS signalling in the biology of cancer[J].Semin Cell Dev Biol,2017,80:50-64.
[52]RUSSELL EG,GUO J,O’SULLIVAN EC,et al.7-Formyl-10-methylisoellipticine,a novel ellipticine derivative,induces mitochondrial reactive oxygen species(ROS)and shows anti-leukaemic activity in mice[J].Invest New Drugs,2016,34(1):15-23.
[53]LEBIEDZINSKA-ARCISZEWSKA M,OPARKAM,VEGA-NAREDO I,et al.The interplay between p66Shc,reactive oxygen species and cancer cell metabolism[J].Eur J Clin Invest,2015,45(Suppl 1):25-31.
[54]LEBIEDZINSKA M,KARKUCINSKA-WIECKOWSKA A,WOJTALA A,et al.Disrupted ATP synthase activity and mitochondrial hyperpolarisationdependent oxidative stress is associated with p66Shc phosphorylation in fibroblasts of NARP patients[J].Int J Biochem Cell Biol,2013,45(1):141-150.
[55]CUI J,GONG Z,SHEN HM.The role of autophagy in liver cancer:molecular mechanisms and potential therapeutic targets[J].Biochim Biophys Acta,2013,1836(1):15-26.
[56]LEI Y,ZHANG D,YU J,et al.Targeting autophagy in cancer stem cells as an anticancer therapy[J].Cancer Lett,2018,416:149.
[57]胡磊,戴海明.线粒体自噬的研究进展[J].中国细胞生物学学报,2018,40(4):594-601.
[58]YAN C,LUO L,GUO CY,et al.Doxorubicininduced mitophagy contributes to drug resistance in cancer stem cells from HCT8human colorectal cancer cells[J].Cancer Lett,2017,388:34-42.
[59]SONG YJ,ZHANG SS,GUO XL,et al.Autophagy contributes to the survival of CD133+liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment[J].Cancer Lett,2013,339(1):70-81.
[60]LI J,CHEN JN,ZENG TT,et al.CD133+liver cancer stem cells resist interferongamma-induced autophagy[J].BMCCancer,2016,16:15.
[61]YANG Y,FAN Y,QI Y,et al.Side population cells separated from A549 lung cancer cell line possess cancer stem cell-like properties and inhibition of autophagy potentiates the cytotoxic effect of cisplatin[J].Oncol Rep,2015,34(2):929-935.
[62]YANG MC,WANG HC,HOU YC,et al.Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine[J].Mol Cancer,2015,14:179.
[63]ZHENG YH,TIAN C,MENG Y,et al.Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells[J].J Cell Physiol,2012,227(1):127-135.