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: Mingxing Wang, Guoyin Li, Zhiwei Yang, Lei Wang, Lei Zhang, Ting Wang, Yimeng Zhang, Shengli Zhang, Yong Han, Lintao Jia
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 5 Pg. 8083-8094 (Jan 31 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28042952 (Publication Type: Journal Article)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Neoplasm Proteins
• PPAR gamma
• Reactive Oxygen Species
• Taxoids
• UCP2 protein, human
• Uncoupling Protein 2
• Docetaxel
• Glucose
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cellular Reprogramming (drug effects)
• Cisplatin (pharmacology)
• Docetaxel
• Dose-Response Relationship, Drug
• Down-Regulation
• Drug Resistance, Neoplasm (genetics)
• Energy Metabolism (drug effects)
• Gene Expression Regulation, Neoplastic
• Glucose (metabolism)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Neoplasm Proteins (genetics, metabolism)
• PPAR gamma (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Taxoids (pharmacology)
• Tumor Hypoxia
• Tumor Microenvironment
• Uncoupling Protein 2 (genetics, metabolism)