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.

RNA SEQ Analysis Indicates that the AE3 Cl−/HCO3 − Exchanger Contributes to Active Transport-Mediated CO2 Disposal in Heart

“…Reduced expression of Pcx (pyruvate carboxylase), which exhibits reduced activity in Drosophila flies adapted to hypoxia 107 , would reduce the conversion of pyruvate to oxaloacetate 108 . The reduction in Ucp2 (uncoupling protein 2), a member of the hypoxia response GO category that is down-regulated by hypoxia via repression of Pparg 109 , would reduce the transport of oxaloacetate and other 4-carbon intermediates out of mitochondria 110 . Thus, both changes would increase the use of pyruvate and other intermediates for oxidative phosphorylation and reduce their use in ATP-utilizing biosynthetic processes.…”

Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features

“…Uncoupling proteins (UCPs) are a family of mitochondrial proteins, which were originally reported to play essential roles in reducing the reactive oxygen species[ 51 , 52 ]. UCP2 plays a role in carcinogenesis in various tissues, including colon cancer, and regulates the responsiveness of carcinomas to chemotherapy[ 53 - 56 ].…”

The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells

“…Common feature of several tumors such as non-small cell lung cancer (NSCLC) is the resistance to radiation and chemotherapy, the specific mechanisms are not entirely understood but it is well known that hypoxia supports the malignancy and the expression of ATP-binding cassette (ABC) transporters, which drive chemotherapeutic agents outside the cells [147][148]. Hypoxic conditions are also combined with down-regulation of mitochondrial uncoupling protein 2 (UCP2) in NSCLC, as highlighted in a recent work [149]. UCP2 is a mitochondrial proteins involved in the detoxification process for reducing ROS levels, because the cells are more sensible to superoxide anion released after proton force development by electron transport chain.…”

“…Down-regulation of UCP2 by hypoxia was associated with PPARγ repression and up-regulation of ABC transporter ABCG2, increasing aerobic glycolysis and chemoresistance. HIF-1 was directly involved in PPARγ and FAO downregulation; this condition negatively affected the UCP2 transcription, conversely glucose consumption was stimulated and a progressive increase of ROS was established in concert with ABCG2 up-regulation [149,151]. Several studies displayed the ability of ATRA (all trans retinoic acid) to induce differentiation of some myelocytic cell lines (HL-60, U937 and NB4) into mature phagocytic cells.…”