title: Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer.
abstract: Hypoxic microenvironment is critically involved in the response of non-small cell lung cancer (NSCLC) to chemotherapy, the mechanisms of which remain largely unknown. Here, we found that NSCLC patients exhibited increased chemotherapeutic resistance when complicated by chronic obstructive pulmonary disease (COPD), a critical cause of chronic hypoxemia. The downregulation of uncoupling protein 2 (UCP2), which is attributed to hypoxia-inducible factor 1 (HIF-1)-mediated suppression of the transcriptional factor peroxisome proliferator-activated receptor γ (PPARγ), was involved in NSCLC chemoresistance, and predicted a poor survival rate of patients receiving routine chemotherapy. UCP2 suppression induced reactive oxygen species production and upregulation of the ABC transporter protein ABCG2, which leads to chemoresistance by promoting drug efflux. UCP2 downregulation also altered metabolic rates as shown by elevated glucose uptake and reduced oxygen consumption. These data suggest that UCP2 is a key mediator of hypoxia-triggered chemoresistance of NSCLCs, which can be potentially targeted in clinical treatment of chemo-refractory NSCLCs.
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Guoyin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Jia
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D043823:Taxoids; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000077143:Docetaxel; D005947:Glucose; D002945:Cisplatin
keywords: PPAR-γ; chemotherapeutic resistance; hypoxia; non-small cell lung cancer (NSCLC); uncoupling protein 2 (UCP2)