UCP2 Inhibits ROS-Mediated Apoptosis in A549 under Hypoxic Conditions

Deng, Sanming; Yang, Yuxiang; Ye, Han; Li, Xiaofei; Wang, Xiaoping; Li, Xueyong; Zhang, Zhipei; Wang, Yunjie

doi:10.1371/journal.pone.0030714

Cited by 67 publications

(51 citation statements)

References 36 publications

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“…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]. UCP2 was also shown to downregulate HIF-1, which, together with our finding that HIF-1 mediated hypoxia-triggered silencing of UCP2, suggests a regulatory circuit between UCP2 and HIF-1 determining the phenotypes of hypoxic malignant cells [10].…”

Section: Discussionsupporting

confidence: 91%

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

Wang

Yang

et al. 2016

Oncotarget

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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.

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Section: Discussionsupporting

confidence: 91%

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

Wang

Yang

et al. 2016

Oncotarget

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“…Our work provides evidence that this task is accomplished by UCP2. The data presented herein are also of interest in cancer research because UCP2 is overexpressed in most cancer cells (33), where it has been shown to have an antiapoptotic function by controlling ROS production (34) and to play a role in the Warburg effect (33,35). The proliferation of cancer cells requires the rapid synthesis of macromolecules requiring a supply of nucleotides, proteins, and lipids.…”

Section: Discussionmentioning

confidence: 87%

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

Vozza

Parisi

Leonardis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

350

372

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Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties. mitochondrial carrier | glucose and glutamine metabolism | Warburg effect | metabolic reprogramming | diabetes M itochondria couple respiratory oxidation of nutrients to ATP synthesis through an electrochemical proton gradient. Proton leak allows partial uncoupling of oxidative phosphorylation, producing heat. Through this mechanism, Uncoupling protein (UCP)1, a member of the mitochondrial carrier family (MCF), regulates adaptive thermogenesis in mammals. In 1997 a protein similar to UCP1 was cloned and named UCP2 (1) based on the assumption that the sequence homology implied a similar function. Whereas UCP1 has a clear-cut uncoupling activity relevant to nonshivering thermogenesis, this is not the case for UCP2. UCP2 has been involved in numerous physiopathological conditions including metabolic disorders, inflammation, ischemic shock, cancer, and aging. Furthermore, changes in UCP2 expression affect metabolic functions (2, 3). It has been suggested that these metabolic actions of UCP2 are due to a mild UCP1-like uncoupling activity (4, 5) that, combined with the generally low levels of UCP2 expression, would regulate the release of reactive oxygen species (ROS) (6) without significantly affecting energy conservation. Although fatty acid-dependent proton transport mediated by UCP2 was reported in reconstituted liposomes (7), a mounting body of evidence argues against UCP2 having an uncoupling activity in vivo (8, 9) and sugge...

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“…ROS are produced by eukaryotic cells during normal oxidative metabolism and cells' antioxidant system scavenges ROS to maintain the redox balance. However, an imbalance between production of ROS and cells antioxidant system's ability to readily detoxify ROS results in oxidative stress (6,7). Glutathione (GSH) is the most abundant intracellular antioxidant involved in the protection of cells against oxidative damage and in various detoxification mechanisms (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

et al. 2012

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Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time‐ and dose‐dependent manner. The alantolactone‐induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl‐2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP‐ribose) polymerase. This alantolactone‐induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N‐acetyl‐L‐cysteine, whereas other antioxidant (polyethylene glycol (PEG)‐catalase and PEG‐superoxide‐dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF‐κB into nucleus; however, NF‐κB inhibitor, SN50 failed to potentiate alantolactone‐induced apoptosis indicating that alantolactone induces NF‐κB‐independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy. © © 2012 IUBMB Life, 64(9): 783–794, 2012

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UCP2 Inhibits ROS-Mediated Apoptosis in A549 under Hypoxic Conditions

Cited by 67 publications

References 36 publications

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

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

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

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