title: Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.
abstract: Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors.
authors.affiliation: Department of Otorhinolaryngology, Research Center, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: H
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Otorhinolaryngology, Research Center, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Otolaryngology, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Otorhinolaryngology, Research Center, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Co-innovation Center of Neuroregeneration, Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China.
authors.forename: R
authors.initials: R
authors.lastname: Chai
authors.affiliation: Department of Otorhinolaryngology, Research Center, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: H
authors.identifier: 0000000233942278
authors.initials: H
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D002945:Cisplatin
references.citation: J Exp Med. 2000 Oct 2;192(7):1001-14
references.pmid: 11015441
references.citation: Cancer Res. 2011 Apr 15;71(8):2978-87
references.pmid: 21467167
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4038-43
references.pmid: 11259653
references.citation: Mol Cell. 2013 Jan 10;49(1):121-32
references.pmid: 23201127
references.citation: Nature. 2013 Jan 31;493(7434):632-7
references.pmid: 23254936
references.citation: PLoS Pathog. 2010;6(12):e1001226
references.pmid: 21187912
references.citation: Nat Cell Biol. 2009 Oct;11(10):1241-6
references.pmid: 19734890
references.citation: Hum Mol Genet. 2004 May 1;13(9):935-44
references.pmid: 15016765
references.citation: Nucleic Acids Res. 2004;32(20):6015-27
references.pmid: 15547250
references.citation: Mitochondrion. 2006 Dec;6(6):299-304
references.pmid: 17098481
references.citation: Oncol Lett. 2013 Oct;6(4):1098-1102
references.pmid: 24137470
references.citation: Science. 2001 Jan 26;291(5504):643-6
references.pmid: 11158675
references.citation: Cell. 1977 Aug;11(4):719-27
references.pmid: 560914
references.citation: Annu Rev Biochem. 1997;66:409-35
references.pmid: 9242913
references.citation: Mol Cell. 2003 Mar;11(3):807-15
references.pmid: 12667461
references.citation: J Biol Chem. 2010 Nov 12;285(46):36199-206
references.pmid: 20841353
references.citation: Science. 2004 Feb 13;303(5660):1010-4
references.pmid: 14963330
references.citation: J Biol Chem. 1992 Jun 5;267(16):10939-41
references.pmid: 1597435
references.citation: Nucleic Acids Res. 2009 Sep;37(17):5701-13
references.pmid: 19625489
references.citation: Science. 1998 Sep 25;281(5385):2027-31
references.pmid: 9748162
references.citation: Cell. 2009 Jun 26;137(7):1247-58
references.pmid: 19563757
references.citation: Oncogene. 2008 Jan 31;27(6):831-8
references.pmid: 17637738
references.citation: Diagn Pathol. 2014;9:28
references.pmid: 24499477
references.citation: PLoS One. 2013;8(3):e57771
references.pmid: 23469236
references.citation: J Genet Genomics. 2009 Mar;36(3):125-31
references.pmid: 19302968
references.citation: Nature. 2001 Mar 29;410(6828):549-54
references.pmid: 11279485
references.citation: Mamm Genome. 2003 Jan;14(1):1-6
references.pmid: 12532263
references.citation: Nucleic Acids Res. 2006;34(20):5815-28
references.pmid: 17062618
references.citation: PLoS One. 2008;3(6):e2459
references.pmid: 18560520
references.citation: Cell Death Differ. 2013 Dec;20(12):1644-53
references.pmid: 23995230
references.citation: Mutat Res. 1992 Jan;265(1):103-48
references.pmid: 1370239