PMID- 29684851 OWN - NLM STAT- MEDLINE DCOM- 20181010 LR - 20181010 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 103 DP - 2018 Jul TI - Mitochondrial DNA content reduction induces aerobic glycolysis and reversible resistance to drug-induced apoptosis in SW480 colorectal cancer cells. PG - 729-737 LID - S0753-3322(18)31019-9 [pii] LID - 10.1016/j.biopha.2018.04.099 [doi] AB - Mutations and reductions in mitochondrial DNA (mtDNA), which are frequent in human tumors, may contribute to enhancing their malignant phenotypes. However, the effects of mtDNA abnormalities in colorectal cancer remain largely unknown. In this study, mtDNA-reduced cell model was established by partial depletion of mtDNA in SW480 cells and the effects of mtDNA reduction in colorectal cancer cells were investigated. We found that mtDNA-reduced cells had enhanced glucose uptake and generated markedly higher level of lactate. These changes were accompanied by only a slight reduction in ATP production compared with the parent cells. Furthermore, the activity of the glycolytic enzymes, hexokinase (HK) and phosphofructokinase (PFK), was increased in mtDNA-reduced cells. These results suggested a switch to aerobic glycolysis in mtDNA-reduced cells, which helped the cells to gain a survival advantage. Notably, when mtDNA content was restored, metabolism returned to normal. In addition, the mtDNA-reduced cells were highly resistant to 5-fluorouracil- and oxaliplatin-induced apoptosis and this drug resistance was reversible following recovery of the mtDNA content. We also found that the Akt/mTOR pathway was activated in the mtDNA-reduced cells. This pathway might play a significant role in drug resistance in the mtDNA-reduced cells as drug susceptibility was restored when this pathway was inhibited. Taken together, our results supported the notion that mtDNA reduction induced aerobic glycolysis and a reversible apoptosis-resistant phenotype in SW480 cells, and that the Akt/mTOR pathway might be involved in the drugs-induced apoptosis resistance. CI - Copyright (c) 2018. Published by Elsevier Masson SAS. FAU - Mou, Jing-Jing AU - Mou JJ AD - Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, PR China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Peng, Jin AU - Peng J AD - Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Shi, Ying-Ying AU - Shi YY AD - Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, PR China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Li, Na AU - Li N AD - Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, PR China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Wang, You AU - Wang Y AD - Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, PR China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Ke, Yuan AU - Ke Y AD - Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, PR China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Zhou, Yun-Feng AU - Zhou YF AD - Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. FAU - Zhou, Fu-Xiang AU - Zhou FX AD - Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, PR China; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, PR China. Electronic address: happyzhoufx@sina.com. LA - eng PT - Journal Article DEP - 20180424 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Antineoplastic Agents) RN - 0 (DNA, Mitochondrial) RN - 0 (Reactive Oxygen Species) SB - IM MH - Antineoplastic Agents/*pharmacology MH - Apoptosis/drug effects/*physiology MH - Cell Line, Tumor MH - Cell Survival/drug effects/physiology MH - Colorectal Neoplasms/*metabolism MH - DNA, Mitochondrial/*metabolism MH - Dose-Response Relationship, Drug MH - Drug Resistance, Neoplasm/drug effects/*physiology MH - Glycolysis/drug effects/*physiology MH - Humans MH - Reactive Oxygen Species/metabolism OTO - NOTNLM OT - Aerobic glycolysis OT - Akt/mTOR pathway OT - Apoptosis resistance OT - SW480 cells EDAT- 2018/04/24 06:00 MHDA- 2018/10/12 06:00 CRDT- 2018/04/24 06:00 PHST- 2018/02/12 00:00 [received] PHST- 2018/04/13 00:00 [revised] PHST- 2018/04/13 00:00 [accepted] PHST- 2018/04/24 06:00 [pubmed] PHST- 2018/10/12 06:00 [medline] PHST- 2018/04/24 06:00 [entrez] AID - S0753-3322(18)31019-9 [pii] AID - 10.1016/j.biopha.2018.04.099 [doi] PST - ppublish SO - Biomed Pharmacother. 2018 Jul;103:729-737. doi: 10.1016/j.biopha.2018.04.099. Epub 2018 Apr 24.