4-Hydroxy-2-nonenal upregulates endogenous antioxidants and phase 2 enzymes in rat H9c2 myocardiac cells: protection against overt oxidative and electrophilic injury

This study was undertaken to determine if 4-hydroxy-2-nonenal (HNE) could upregulate antioxidants and phase 2 enzymes in rat H9c2 myocardiac cells, and if the upregulated defenses led to cytoprotection against oxidative and electrophilic injury. Incubation of H9c2 cells with HNE at noncytotoxic concentrations resulted in significant induction of cellular catalase, glutathione (GSH), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1), as determined by enzyme activity and/or protein expression. HNE treatment caused increased mRNA expression of catalase, γ-glutamylcysteine ligase, GST-A1, and NQO1. Pretreatment of H9c2 cells with HNE led to significant protection against cytotoxicity induced by reactive oxygen and nitrogen species. HNE-pretreated cells also exhibited increased resistance to injury elicited by subsequent cytotoxic concentrations of HNE. Taken together, this study demonstrates that several antioxidants and phase 2 enzymes in H9c2 cells are upregulated by HNE and that the increased defenses afford protection against overt oxidative and electrophilic cardiac cell injury.     

Role of antioxidants in protecting cellular DNA from damage by oxidative stress

We have previously derived 2 V79 clones resistant to menadione (Md1 cells) and cadmium (Cd1 cells), respectively. They both were shown to be cross-resistant to hydrogen peroxide. There was a modification in the antioxidant repertoire in these cells as compared to the parental cells. Md1 presented an increase in catalase and glutathione peroxidase activities whereas Cd1 cells exhibited an increase in metallothionein and glutathione contents. The susceptibility of the DNA of these cells to the damaging effect of H₂O₂ was tested using the DNA precipitation assay. Both Md1 and Cd1 DNAs were more resistant to the peroxide action. In the case of Md1 cells it seems clear that the extra resistance is provided by the increase in the two H₂O₂ scavenger enzymes, catalase and glutathione peroxidase. In the case of Cd1 cells the activities of these enzymes as well as of superoxide dismutases (Cu/Zn and Mn) are unaltered as compared to the parental cells. The facts that parental cells exposed to 100 μM Zn²⁺ in the medium exhibit an increase in metallothionein but not in glutathione and that these cells become more resistant to the DNA-damaging effect of H₂O₂ suggest that this protein might play a protective role in vivo against the OH radical attack on DNA.     

Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress

Macrophages play important roles in immunity and other physiological processes. They are also target cells of various toxic agents, including oxidants and electrophiles. However, little is known regarding the molecular regulation and chemical inducibility of a spectrum of endogenous antioxidants and phase 2 enzymes in normal macrophages. Understanding the molecular pathway(s) controlling the coordinated expression of various macrophage antioxidants and phase 2 defenses is of importance for developing strategies to protect against macrophage injury induced by oxidants and electrophiles. Accordingly, this study was undertaken to determine the role of the nuclear factor E2-related factor 2 (Nrf2) in regulating both constitutive and chemoprotectant-inducible expression of various antioxidants and phase 2 enzymes in mouse macrophages. The constitutive expression of a series of antioxidants and phase 2 enzymes was significantly lower in macrophages derived from Nrf2-null (Nrf2(-/-)) mice than those from wild-type (Nrf2(+/+)) littermates. Incubation of wild-type macrophages with 3H-1,2-dithiole-3-thione (D3T) led to significant induction of various antioxidants and phase 2 enzymes, including catalase, glutathione, glutathione peroxidase (GPx), glutathione reductase, glutathione S-transferase, and NAD(P)H:quinone oxidoreductase 1. The inducibility of the above cellular defenses except for GPx by D3T was completely abolished in Nrf2(-/-) macrophages. As compared with wild-type cells, Nrf2(- /-) macrophages were much more susceptible to cell injury induced by reactive oxygen/nitrogen species, as well as two known macrophage toxins, acrolein and cadmium. Up-regulation of the antioxidants and phase 2 enzymes by D3T in wild-type macrophages resulted in increased resistance to the above oxidant-and electrophile-induced cell injury, whereas D3T treatment of Nrf2(- /-) macrophages provided only marginal or no cytoprotec-tion. This study demonstrates that Nrf2 is an indispensable factor in controlling both constitutive and inducible expression of a wide spectrum of antioxidants and phase 2 enzymes in macrophages as well as the susceptibility of these cells to oxidative and electrophilic stress.     

Induction of endogenous antioxidants and phase 2 enzymes by alpha-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury

Alpha-lipoic acid (LA) has recently been reported to exert protective effects on various forms of oxidative cardiac disorders. However, the mechanisms underlying LA-mediated cardioprotection remain to be investigated. This study was undertaken to determine whether LA treatment could increase endogenous antioxidants and phase 2 enzymes in cultured cardiomyocytes, and whether such increased cellular defenses could afford protection against oxidative cardiac cell injury. Incubation of rat cardiac H9C2 cells with low micromolar concentrations of LA resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These include catalase, reduced glutathione, glutathione reductase, glutathione S-transferase, and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Induction of catalase and NOQ1 was most dramatic among the above LA-inducible antioxidants and phase 2 enzymes. To further investigate the protective effects of the LA-induced cellular defenses on oxidative cardiac cell injury, H9C2 cells were pretreated with LA (25-100 microM) for 72h and then exposed to xanthine oxidase (XO)/xanthine, a system that generates reactive oxygen species (ROS), for another 24h. We observed that LA pretreatment of H9C2 cells led to a marked protection against XO/xanthine-mediated cytotoxicity, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. The cytoprotective effects also exhibited a LA concentration-dependent fashion. Moreover, the LA pretreatment resulted in a great inhibition of intracellular accumulation of ROS in H9C2 cells following incubation with XO/xanthine. Taken together, this study demonstrates for the first time that a number of endogenous antioxidants and phase 2 enzymes in cultured cardiomyocytes can be induced by LA at low micromolar concentrations, and that the LA-mediated elevation of cellular defenses is accompanied by a markedly increased resistance to ROS-elicited cardiac cell injury. The results of this study have important implications for the cardioprotective effects of LA.     

Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes

PURPOSE OF REVIEW: In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications; therefore an antioxidant therapy would be of great interest in this disease. RECENT FINDINGS: Hyperglycemia directly promotes an endothelial dysfunction--inducing process of overproduction of superoxide at the mitochondrial level. This is the first and key event able to activate all the pathways involved in the development of vascular complications of diabetes. It has recently been shown that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones have a strong intracellular antioxidant activity. SUMMARY: Classic antioxidants, such as vitamin E, failed to show beneficial effects on diabetic complications probably because their action is only "symptomatic". The preventive activity against hyperglycemia-induced oxidative stress shown by statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones justifies use of these compounds for preventing complications in patients with diabetes, in whom antioxidant defences have been shown to be defective.     

Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells

Angiotensin II (Ang II)-induced activation of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase leads to increased production of reactive oxygen species (ROS), an important intracellular second messenger in renal disease. Recent findings suggest that Ang II induces mitochondrial depolarization and further amplifies mitochondrial generation of ROS. We examined the hypothesis that ROS injury mediated by Ang II-induced mitochondrial Nox4 plays a pivotal role in mitochondrial dysfunction in tubular cells and is related to cell survival. In addition, we assessed whether angiotensin (1-7) peptide (Ang-(1-7)) was able to counteract Ang II-induced ROS-mediated cellular injury. Cultured NRK-52E cells were stimulated with 10(-6) M Ang II for 24 h with or without Ang-(1-7) or apocynin. Ang II simulated mitochondrial Nox4 and resulted in the abrupt production of mitochondrial superoxide (O(2) (-)) and hydrogen peroxide (H(2)O(2)). Ang II also induced depolarization of the mitochondrial membrane potential, and cytosolic secretion of cytochrome C and apoptosis-inducing factor (AIF). Ang-(1-7) attenuated Ang II-induced mitochondrial Nox4 expression and apoptosis, and its effect was comparable to that of the NAD(P)H oxidase inhibitor. These findings suggest that Ang II-induced activation of mitochondrial Nox4 is an important endogenous source of ROS, and is related to cell survival. The ACE2-Ang-(1-7)-Mas receptor axis should be investigated further as a novel target of Ang II-mediated ROS injury.     

Lipotoxicity in renal proximal tubular cells: Relationship between endoplasmic reticulum stress and oxidative stress pathways

Hyperlipidemia in the general population has been linked to the development of chronic kidney disease with both oxidative and endoplasmic reticulum stress implicated. Physiological levels (50-300 µmol/L) of saturated fatty acids such as palmitic acid (PA) cause cytotoxicity in vitro. We investigated cell type- and stimulus-specific signaling pathways induced by PA in renal proximal tubular cells and whether oxidative stress leads to ER stress or vice versa and which pathways predominate in signaling for PA-induced apoptosis and necrosis. NRK-52E cells were incubated with PA or hydrogen peroxide (H₂O₂) combined with SP600125 which blocks c-Jun N-terminal kinase (JNK) activation; salubrinal, which maintains eukaryotic initiation factor 2α in its phosphorylated state and the antioxidant EUK-134 - a superoxide dismutase mimetic with catalase activity. We found that (i) PA causes both oxidative and ER stress leading to apoptosis which is mediated by phosphorylated JNK; (ii) oxidant-induced apoptosis generated by H₂O₂ involves ER stress signaling and CHOP expression; (iii) the ER stress mediated by PA is largely independent of oxidative stress; (iv) in contrast, the apoptosis produced by PA is mediated partly via oxidative stress. PA-mediated cell signaling in renal NRK-52E cells therefore differs from that identified in neuronal, hepatic and pancreatic beta cells.     

Actinobacteria isolated from termite guts as a source of novel oxidative enzymes

A multi-faceted screening programme was designed to search for the oxidases, laccase, peroxidase and tyrosinase. Actinobacteria were selectively isolated from the paunch and colon region of the hindguts of the higher termite, Amitermes hastatus. The isolates were subjected to solid media assays (dye decolourization, melanin production and the utilization of indulin AT as sole carbon source) and liquid media assays. Eleven of the 39 strains had the ability to decolourize the dye RBBR, an indicator for the production of peroxidases in actinobacteria. Melanin production on ISP6 and ISP7 agar plates served as a good indicator for laccase and/or tyrosinase production and the ability of the strains to grow in the presence of indulin AT as a sole carbon source served as a good indicator of lignin peroxidase and/or general peroxidase production. Enzyme-producing strains were cultivated in liquid media and extracellular enzyme activities measured. Strains with the ability to produce oxidative enzymes under the conditions tested were identified to genus level by 16S rRNA gene analysis and compared to known oxidase producers. A strong relationship was observed between the environment sampled (termite guts where lignocellulose degradation occurs) and the dominant type of oxidative enzyme activity detected (laccases and peroxidases), which suggests the possibility of future targeted screening protocols linking the physical properties of the target enzymes with specific operational conditions required, such as lignocellulosic degradation in the preparation of biofuel feedstocks.     

Cryptotanshinone inhibits hypoxia/reoxygenation-induced oxidative stress and apoptosis in renal tubular epithelial cells

Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge , was reported to attenuate hepatic ischemia/reperfusion (I/R) injury. However, its protective effect against renal I/R injury remains unclear. In this study, the role of CTS in renal I/R injury in vitro and its possible mechanism were investigated. Our results showed that CTS improved cell viability in HK-2 cells exposed to hypoxia/reoxygenation (H/R). CTS also inhibited the H/R-mediated production of reactive oxygen species, as well as increased the activities of superoxide dismutase and catalase in H/R-stimulated HK-2 cells. In addition, CTS dramatically attenuated the induction of bax expression and caspase-3 activity and alleviated the reduction of bcl-2 expression in HK-2 cells cultured with H/R. Furthermore, CTS activated the levels of p-PI3K and p-Akt in H/R-injured HK-2 cells; meanwhile, the renal protective activity of CTS was inhibited by the inhibitor of the (phosphatidylinositol 3 kinase/protein kinase B) PI3K/Akt pathway (LY294002). These findings indicate that CTS can ameliorate renal I/R injury in vitro partly through regulating the PI3K/Akt pathway.     

Upregulation of endogenous glutathione system by 3H-1,2-dithiole-3-thione in pancreatic RINm5F beta-cells as a novel strategy for protecting against oxidative beta-cell injury

This study was undertaken to investigate the inducibility of glutathione (GSH), glutathione reductase (GR) and glutathione peroxidase (GPx) by 3H-1,2-dithiole-3-thione (D3T) in beta-cells, and the resultant cytoprotection against oxidant injury. Incubation of the insulin-secreting RINm5F cells with D3T led to significant induction of GSH, GR and GPx. D3T-mediated induction of GSH was abolished by buthionine sulfoximine (BSO), suggesting a critical involvement of γ-glutamylcysteine ligase (γGCL). Consistently, incubation of RINm5F cells with D3T resulted in increased expression of γGCL protein and mRNA. Pretreatment of RINm5F cells with D3T provided remarkable protection against oxidant-elicited cytotoxicity. On the other hand, depletion of cellular GSH by BSO sensitized RINm5F cells to oxidant injury. Furthermore, cotreatment of RINm5F cells with BSO to reverse D3T-mediated GSH induction abolished the cytoprotective effects of D3T on oxidant injury. Taken together, this study demonstrates that upregulation of glutathione system by D3T is effective for protecting against oxidative beta-cell injury.     

Upregulation of endogenous glutathione system by 3H-1,2-dithiole-3-thione in pancreatic RINm5F beta-cells as a novel strategy for protecting against oxidative beta-cell injury

This study was undertaken to investigate the inducibility of glutathione (GSH), glutathione reductase (GR) and glutathione peroxidase (GPx) by 3H-1,2-dithiole-3-thione (D3T) in beta-cells, and the resultant cytoprotection against oxidant injury. Incubation of the insulin-secreting RINm5F cells with D3T led to significant induction of GSH, GR and GPx. D3T-mediated induction of GSH was abolished by buthionine sulfoximine (BSO), suggesting a critical involvement of γ-glutamylcysteine ligase (γGCL). Consistently, incubation of RINm5F cells with D3T resulted in increased expression of γGCL protein and mRNA. Pretreatment of RINm5F cells with D3T provided remarkable protection against oxidant-elicited cytotoxicity. On the other hand, depletion of cellular GSH by BSO sensitized RINm5F cells to oxidant injury. Furthermore, cotreatment of RINm5F cells with BSO to reverse D3T-mediated GSH induction abolished the cytoprotective effects of D3T on oxidant injury. Taken together, this study demonstrates that upregulation of glutathione system by D3T is effective for protecting against oxidative beta-cell injury.     

Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants.

The responses to oxidative stress induced by chronic exercise (8-wk treadmill running) or acute exercise (treadmill running to exhaustion) were investigated in the brain, liver, heart, kidney, and muscles of rats. Various biomarkers of oxidative stress were measured, namely, lipid peroxidation [malondialdehyde (MDA)], protein oxidation (protein carbonyl levels and glutamine synthetase activity), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine), and endogenous antioxidants (ascorbic acid, alpha-tocopherol, glutathione, ubiquinone, ubiquinol, and cysteine). The predominant changes are in MDA, ascorbic acid, glutathione, cysteine, and cystine. The mitochondrial fraction of brain and liver showed oxidative changes as assayed by MDA similar to those of the tissue homogenate. Our results show that the responses of the brain to oxidative stress by acute or chronic exercise are quite different from those in the liver, heart, fast muscle, and slow muscle; oxidative stress by acute or chronic exercise elicits different responses depending on the organ tissue type and its endogenous antioxidant levels.     

Role of peroxiredoxin-2 in protecting RBCs from hydrogen peroxide-induced oxidative stress

Abstract

The role of peroxiredoxin-2 (PRDX2) in preventing hydrogen peroxide-induced oxidative stress in the red blood cell was investigated by comparing blood from PRDX2 knockout mice with superoxide dismutase-1 (SOD1) knockout and control mice. Loss of PRDX2 increased basal levels of methemoglobin and heme degradation (a marker for oxidative stress), and reduced red blood cell deformability. In vitro incubation under normoxic conditions, both with and without inhibition of catalase, resulted in a lag phase during which negligible heme degradation occurred followed by a more rapid rate of heme degradation in the absence of PRDX2. The appreciable basal increase in heme degradation for PRDX2 knockout mice, together with the lag during in vitro incubation, implies that PRDX2 neutralizes hydrogen peroxide generated in vivo under the transient hypoxic conditions experienced as the cells pass through the microcirculation.     

Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells

Induction of heme oxygenase-1 (HO-1) may serve as an immediate protective response during treatment with the cytostatic drug cisplatin (CDDP). Oxidative pathways participate in the characteristic nephrotoxicity of CDDP. In the present study, cultured tubular cells (LLC-PK1) were used to investigate whether induction of HO provided protection against CDDP by maintaining the cellular redox balance. The antioxidants, alpha-tocopherol (TOCO) and N-acetylcysteine (NAC), were used to demonstrate that elevation of ROS levels contribute to the development of CDDP-induced cytotoxicity. Chemical modulators of HO activity were used to investigate the role of HO herein. Hemin was used to specifically induce HO-1, while exposure of the cells to tin-protoporphyrin (SnPP) was shown to inhibit HO activity. Hemin treatment prior to CDDP-exposure significantly decreased the generation of ROS to control levels, while inhibition of HO increased the ROS levels beyond the levels measured in cells treated with CDDP alone. Furthermore, HO induction protected significantly against the cytotoxicity of CDDP, although this protection was limited. Similar results were obtained when the cells were preincubated with TOCO, suggesting that mechanisms other than impairment of the redox ratio are important in CDDP-induced loss of cell viability in vitro. In addition, SnPP treatment exacerbated the oxidative response and cytotoxicity of CDDP, especially at low CDDP concentrations. We therefore conclude that HO is able to directly limit the CDDP-induced oxidative stress response and thus serves as safeguard of the cellular redox balance.     

Effects of oxidants and antioxidants evaluated using parinaric acid as a sensitive probe for oxidative stress

Parinaric acid (PnA) is a fluorescent polyunsaturated fatty acid which can be used as a probe to study lipid peroxidation processes. The basic methodology is simple and sensitive, and offers a direct ‘view’ of the oxidative decay of a fatty acid and the effects of prooxidant and antioxidant factors. A distinctive feature of the PnA assay is that it does not measure a lipid peroxidation end product, but monitors lipid oxidative stress in its initial stages. This review highlights the methodological characteristics of the PnA assay, and describes the various applications in which PnA and PnA derivatives have yielded useful information. These applications range from oxidant and antioxidant studies in lipid model systems to comparative studies of oxidation processes in normal and pathological red blood cells, and also include studies of lipoprotein oxidation.     

The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress

In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.     

Action of 6-amino-3-pyridinols as novel antioxidants against free radicals and oxidative stress in solution,plasma, and cultured cells

Free radical-mediated lipid peroxidation has been implicated in the pathogenesis of various diseases. Lipid peroxidation products are cytotoxic and they modify proteins and DNA bases, leading eventually to degenerative disorders. Various synthetic antioxidants have been developed and assessed for their capacity to inhibit lipid peroxidation and oxidative stress induced by free radicals. In this study, the capacity of novel 6-amino-2,4,5-trimethyl-3-pyridinols for scavenging peroxyl radicals, inhibiting plasma lipid peroxidation in vitro, and preventing cytotoxicity induced by glutamate, 6-hydroxydopamine, 1-methyl-4-phenylpyridium (MPP⁺ ), and hydroperoxyoctadecadienoic acid was assessed. It was found that they exerted higher reactivity toward peroxyl radicals and more potent activity for inhibiting the above oxidative stress than α-tocopherol, the most potent natural antioxidant, except against the cytotoxicity induced by MPP⁺. These results suggest that the novel 6-amino-3-pyridinols may be potent antioxidants against oxidative stress.     

Longevity and antioxidant enzymes,non-enzymatic antioxidants and oxidative stress in the vertebrate lung: a comparative study

It has been proposed that antioxidants can be longevity determinants in animals. However, no comprehensive study has been conducted to try to relate free radicals with maximum life span. This study compares the lung tissue of various vertebrate species — amphibia, mammals and birds — showing very different and well known maximum life spans and life energy potentials. The lung antioxidant enzymes superoxide dismutase, catalase, Se-dependent and non-Se-dependent glutathione peroxidases, and glutathione reductase showed significantly negative correlations with maximum life span. The same was observed for the lung antioxidants, reduced glutathione and ascorbate. It is concluded that a generalized decrease in tissue antioxidant capacity is a characteristic of longevous species. It is suggested that a low rate of free radical recycling (free-radical generation and scavenging) can be an important factor involved in the evolution of high maximum animal longevities. A low free-radical production could be responsible for a low rate of damage at critical sites such as mitochondrial DNA.Abbreviations CAT catalase - COX cytochrome oxidase - GPx glutathione peroxidase - GR glutathione reductase - GSH reduced glutathione - GSSG oxidized glutathione - LEP life energy potential - MDA malondialdehyde - MLSP maximum life span - MR metabolic rate - MW molecular weight - PO₂ partial pressure of oxygen - SOD superoxide dismutase - VO₂ basal oxygen consumption     

SOX2 as a novel contributor of oxidative metabolism in melanoma cells

Background

Deregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome. Despite the general attitude of cancer cells to exploit the glycolytic pathway even in the presence of oxygen (aerobic glycolysis or “Warburg effect”), tumor metabolism is extremely plastic, and such ability to switch from glycolysis to oxidative phosphorylation (OxPhos) allows cancer cells to survive under hostile microenvironments. Recently, OxPhos has been related with malignant progression, chemo-resistance and metastasis. OxPhos is induced under extracellular acidosis, a well-known characteristic of most solid tumors, included melanoma.

Methods

To evaluate whether SOX2 modulation is correlated with metabolic changes under standard or acidic conditions, SOX2 was silenced and overexpressed in several melanoma cell lines. To demonstrate that SOX2 directly represses HIF1A expression we used chromatin immunoprecipitation (ChIP) and luciferase assay.

Results

In A375-M6 melanoma cells, extracellular acidosis increases SOX2 expression, that sustains the oxidative cancer metabolism exploited under acidic conditions. By studying non-acidic SSM2c and 501-Mel melanoma cells (high- and very low-SOX2 expressing cells, respectively), we confirmed the metabolic role of SOX2, attributing SOX2-driven OxPhos reprogramming to HIF1α pathway disruption.

Conclusions

SOX2 contributes to the acquisition of an aggressive oxidative tumor phenotype, endowed with enhanced drug resistance and metastatic ability.