Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

Abstract

// Mingxing Wang 1, * , Guoyin Li 2, * , Zhiwei Yang 3, * , Lei Wang 2 , Lei Zhang 3 , Ting Wang 2 , Yimeng Zhang 2 , Shengli Zhang 3 , Yong Han 1 , Lintao Jia 2 1 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China 2 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China 3 Department of Applied Physics, Xi’an Jiaotong University, Xi’an, China * These authors have contributed equally to this work. Correspondence to: Yong Han, email: hanyongmd@yahoo.com Lintao Jia, email: jialth@fmmu.edu.cn Keywords: uncoupling protein 2 (UCP2), non-small cell lung cancer (NSCLC), chemotherapeutic resistance, hypoxia, PPAR-γ Received: July 16, 2016     Accepted: November 22, 2016     Published: December 22, 2016 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.