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.
Highlights
Non-small cell lung cancer (NSCLC), which is among the leading causes of cancer mortality worldwide, is characterized by relative insensitivity to radiation and chemotherapy [1]
uncoupling protein 2 (UCP2) deficiency facilitated the development of chemoresistance via refractory apoptosis and the reprogramming of glucose metabolism in non-small cell lung cancer (NSCLC) cells exposed to chemotherapy
Despite the apparent discrepancies concerning the role of UCP2 in carcinogenesis and cancer progression in different types of cells, e.g. UCP2 inhibition of apoptosis in hypoxia, our findings are in accordance with recent reports that UCP2 represses the malignant phenotypes of melanoma, glioma, and pancreatic cancer cells and that UCP2 deficiency mimics the effects of hypoxia in pulmonary hypertension [10, 11, 24, 25]
Summary
Non-small cell lung cancer (NSCLC), which is among the leading causes of cancer mortality worldwide, is characterized by relative insensitivity to radiation and chemotherapy [1]. Chemoresistant cells are characterized by increased activity of specific growth factor pathways or constitutive activation of downstream kinases involved in proliferative or survival signaling, defects in the apoptotic machinery, and the overexpression of membrane transporters, e.g., ATP-binding cassette (ABC) transporters, which function as outward pumps for chemotherapeutic drugs [2, 3]. The hallmark of hypoxia in neoplastic cells is the expression of hypoxia-inducible factor (HIF). As a master regulator of oxygen homeostasis, HIF-1 induces the expression of hypoxia-responsive genes involved in the survival and www.impactjournals.com/oncotarget mitosis of carcinoma cells. HIF-1 is required for the maintenance of malignant phenotypes, such as the self-renewal of cancer stem cells and resistance to anticancer therapeutics [6]. The key mediators and cellular events associated with hypoxia-induced chemotherapy resistance remain to be defined
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