Redox Homeostasis In Cancer Research Articles

Repurposed genipin targeting UCP2 exhibits antitumor activity through inducing ferroptosis in glioblastoma.

Uncoupling protein-2 (UCP2) controls the antioxidant response and redox homeostasis in cancer and is considered a potent molecular target for cancer treatment. However, the specific mechanism of UCP2 inhibition and its role in glioblastoma (GBM) have not yet been elucidated. Here, we attempt to identify a UCP2 inhibitor and study the underlying molecular mechanism in GBM. Bioinformatics analysis and immunohistochemistry are used to validate the high expression of UCP2 in GBM and its prognostic significance. Drug intervention and tumor xenograft experiments are conducted to determine the inhibitory effect of genipin, a UCP2 inhibitor, on UCP2. The mitochondrial membrane potential and key ferroptosis genes are examined to determine the occurrence of ferroptosis. High expression of UCP2 in GBM is associated with poor prognosis, and inhibiting UCP2 can alleviate the malignant behavior of GBM tumors. Genipin can downregulate the expression of GPX4 and upregulate the expression of ACSL4 by inhibiting UCP2, leading to ferroptosis and alleviating the malignant behavior of tumors. In summary, UCP2 is a potential therapeutic target for GBM. Genipin, which targets UCP2, effectively inhibits GBM development by inducing ferroptosis in vivo and in vitro. These findings indicate that genipin treatment based on UCP2 targeting has potential therapeutic applications with a clinical perspective for the treatment of GBM patients.

Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.

Recent Advances in Cellular Signaling Interplay between Redox Metabolism and Autophagy Modulation in Cancer: An Overview of Molecular Mechanisms and Therapeutic Interventions

Autophagy is a fundamental homeostatic process in which certain cellular components are ingested by double-membrane autophagosomes and then degraded to create energy or to maintain cellular homeostasis and survival. It is typically observed in nutrient-deprived cells as a survival mechanism. However, it has also been identified as a crucial process in maintaining cellular homeostasis and disease progression. Normal cellular metabolism produces reactive oxygen (ROS) and nitrogen species at low levels. However, increased production causes oxidative stress, which can lead to diabetes, cardiovascular diseases, neurological disorders, and cancer. It was recently shown that maintaining redox equilibrium via autophagy is critical for cellular responses to oxidative stress. However, little is understood about the molecular cancer processes that connect to the control of autophagy. In cancer cells, oncogenic mutations, carcinogens, and metabolic reprogramming cause increased ROS generation and oxidative stress. Recent studies have suggested that increased ROS generation activates survival pathways that promote cancer development and metastasis. Moreover, the relationship between metabolic programming and ROS in cancer cells is involved in redox homeostasis and the malignant phenotype. Currently, while the signaling events governing autophagy and how redox homeostasis affects signaling cascades are well understood, very little is known about molecular events related to autophagy. In this review, we focus on current knowledge about autophagy modulation and the role of redox metabolism to further the knowledge of oxidative stress and disease progression in cancer regulation. Therefore, this review focuses on understanding how oxidation/reduction events fine-tune autophagy to help understand how oxidative stress and autophagy govern cancer, either as processes leading to cell death or as survival strategies for maintaining redox homeostasis in cancer.

Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone.

IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.

Role of Phytochemicals in Perturbation of Redox Homeostasis in Cancer.

Over the past few decades, research on reactive oxygen species (ROS) has revealed their critical role in the initiation and progression of cancer by virtue of various transcription factors. At certain threshold values, ROS act as signaling molecules leading to activation of oncogenic pathways. However, if perturbated beyond the threshold values, ROS act in an anti-tumor manner leading to cellular death. ROS mediate cellular death through various programmed cell death (PCD) approaches such as apoptosis, autophagy, ferroptosis, etc. Thus, external stimulation of ROS beyond a threshold is considered a promising therapeutic strategy. Phytochemicals have been widely regarded as favorable therapeutic options in many diseased conditions. Over the past few decades, mechanistic studies on phytochemicals have revealed their effect on ROS homeostasis in cancer. Considering their favorable side effect profile, phytochemicals remain attractive treatment options in cancer. Herein, we review some of the most recent studies performed using phytochemicals and, we further delve into the mechanism of action enacted by individual phytochemicals for PCD in cancer.

Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.

The Central Role of Amino Acids in Cancer Redox Homeostasis: Vulnerability Points of the Cancer Redox Code.

A fine balance in reactive oxygen species (ROS) production and removal is of utmost importance for homeostasis of all cells and especially in highly proliferating cells that encounter increased ROS production due to enhanced metabolism. Consequently, increased production of these highly reactive molecules requires coupling with increased antioxidant defense production within cells. This coupling is observed in cancer cells that allocate significant energy reserves to maintain their intracellular redox balance. Glutathione (GSH), as a first line of defense, represents the most important, non-enzymatic antioxidant component together with the NADPH/NADP+ couple, which ensures the maintenance of the pool of reduced GSH. In this review, the central role of amino acids (AAs) in the maintenance of redox homeostasis in cancer, through GSH synthesis (cysteine, glutamate, and glycine), and nicotinamide adenine dinucleotide (phosphate) production (serine, and glutamine/glutamate) are illustrated. Special emphasis is placed on the importance of AA transporters known to be upregulated in cancers (such as system xc-light chain and alanine-serine-cysteine transporter 2) in the maintenance of AA homeostasis, and thus indirectly, the redox homeostasis of cancer cells. The role of the ROS varies (often described as a “two-edged sword”) during the processes of carcinogenesis, metastasis, and cancer treatment. Therefore, the context-dependent role of specific AAs in the initiation, progression, and dissemination of cancer, as well as in the redox-dependent sensitivity/resistance of the neoplastic cells to chemotherapy are highlighted.

Abstract 4787: The role of CaMK2A in reactive oxygen species homeostasis in lung adenocarcinoma

Abstract The role of Calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) in reactive oxygen species homeostasis in lung adenocarcinoma Lung cancer is the most common cancer worldwide and patients have poor prognosis and low survival rate. The unsatisfactory outcomes of lung cancer treatment are related to multiple factors including tumor recrudescence, metastasis, cancer drug resistance, etc. Cancer stem cells are cell subsets within a cancer that excel in tumor properties, especially survival, renewal and resistance to treatment. Reactive oxygen species (ROS) are high energy molecules produced during cellular hyperproliferation and cell death. Studies have shown though a low level of ROS is required to support stem cell functions but excessive ROS damages DNA and predisposes to cell death. Therefore, the ability to attenuate oxidative damage from ROS and maintain redox homeostasis is an important property of aggressive and resilient cancer cells. The multifunctional serine/threonine kinase calcium/calmodulin- dependent protein kinase II alpha (CaMK2A) is a calcium signaling molecule involved in cell growth and stress signals integration. It has been reported to play a tumor-supportive role in osteosarcoma, prostate cancer and leukemia. However, little is known about the impact and mechanisms of CaMK2A on lung cancer and cancer redox homeostasis. This study aims to investigate the role of CaMK2A in ROS regulation in lung cancer stem cells. We measured ROS levels using H2DCFDA probes in cancer stem cells isolated from two lung cancer cell lines by the known lung cancer stem cell marker CD44 and CD166. Compared to CD44- and CD166- non-stem cells, ROS levels were lower in both CD44+ and CD166+ cancer stem cells. In cancer cells with stable CaMK2A knockdown by shRNA (CaMK2A-KD), ROS was suppressed while CaMK2A overexpression led to ROS elevation, suggesting a potential role of CaMK2A on ROS regulation in lung cancer stem cells. To understand the mechanism, activated NRF2 levels, the master transcription factor mediating ROS regulation, were measured in total nuclear protein extracts. By Western blot, nuclear NRF2 protein showed upregulation in CaMK2A overexpression cells and decreased levels in CaMK2A-KD cells, implying NRF2 might be a mediator of CaMK2A in ROS regulation. To further identify downstream regulators, mRNA expression analysis of five ROS-regulatory NRF2 target genes (GSTP1, NQO1, GCLC, HMOX1, TRXR1) was performed. Quantitative PCR results showed significant corresponding changes of some these gene expressions in cell lines, which upregulated in CaMK2A overexpression and downregulated in both CaMK2A-KD cells and CaMK2A pharmacological inhibition cells. Together, the results indicate CaMK2A might regulate ROS status through mediating downstream target genes of NRF2. Citation Format: Siqi Wang, Zhijie Xiao, Vicky Tin, Ian K. Lam, Xuyuan Gao, Maria Wong. The role of CaMK2A in reactive oxygen species homeostasis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2017-4787

PFKFB3 Regulates Oxidative Stress Homeostasis via Its S-Glutathionylation in Cancer

Whereas moderately increased cellular oxidative stress is supportive for cancerous growth of cells, excessive levels of reactive oxygen species (ROS) are detrimental to their growth and survival. We demonstrated that high ROS levels, via increased oxidized glutathione (GSSG), induce isoform-specific S-glutathionylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) at residue Cys206, which is located near the entrance to the 6-phosphofructo-2-kinase catalytic pocket. Upon this ROS-dependent, reversible, covalent modification, a marked decrease in its catalytic ability to synthesize fructose-2,6-bisphosphate (Fru-2,6-P2), the key glycolysis allosteric activator, was observed. This event was coupled to a decrease in glycolytic flux and an increase in glucose metabolic flux into the pentose phosphate pathway. This shift, in turn, caused an increase in reduced glutathione (GSH) and, ultimately, resulted in ROS detoxification inside HeLa cells. The ability of PFKFB3 to control the Fru-2,6-P2 levels in an ROS-dependent manner allows the PFKFB3-expressing cancer cells to continue energy metabolism with a reduced risk of excessive oxidative stress and, thereby, to support their cell survival and proliferation. This study provides a new insight into the roles of PFKFB3 as switch that senses and controls redox homeostasis in cancer in addition to its role in cancer glycolysis.

Understanding Redox Homeostasis and Its Role in Cancer

When a cell is damaged or altered without repair to its system, it usually dies. But if such damaged or unrepaired cells do not die and proliferate with uncontrolled growth; a mass of cancer cells develop. Cancer has a complex aetiology with multiple risk factors that involve the interplay between genetic and environmental influences. The redox dysregulation originates from metabolic alterations and it is dependent on mitogenic and survival signalling through reactive oxygen species. There is a delicate balance between the production and the destruction of reactive species; for this, we need to understand the role of redox homeostasis in cancer. So, the specific vulnerability of the malignant cells can be selectively targeted. This article will outline the redox homeostasis and the relationship between the disturbances in it and cancer.

Effect of high oxygen concentrations on eyes of newborn mice.

ArticleEffect of High Oxygen Concentrations on Eyes of Newborn MiceRebeca Gerschman, Perry W. Nadig, Albert C. Snell JR., and Sylvanus W. NyeRebeca GerschmanFrom the Departments of Physiology and Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, Perry W. NadigFrom the Departments of Physiology and Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, Albert C. Snell JR.From the Departments of Physiology and Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, and Sylvanus W. NyeFrom the Departments of Physiology and Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New YorkPublished Online:01 Oct 1954https://doi.org/10.1152/ajplegacy.1954.179.1.115MoreSectionsPDF (866 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByHIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease15 June 2021 | Journal of Clinical Investigation, Vol. 131, No. 12Animal Models of Retinopathy of Prematurity19 January 2021Delayed Onset of Retinopathy of Prematurity Associated With Mitochondrial Dysfunction and Pearson SyndromeJournal of Pediatric Ophthalmology & Strabismus, Vol. 56The Central Role of Amino Acids in Cancer Redox Homeostasis: Vulnerability Points of the Cancer Redox Code21 December 2017 | Frontiers in Oncology, Vol. 7Models of Oxygen Induced Retinopathy in Rodents13 May 2016Bevacizumab Revisited: Its Use in Different Mouse Models of Ocular Pathologies12 August 2014 | Current Eye Research, Vol. 40, No. 6Effect of decreasing target oxygen saturation on retinopathy of prematurityJournal of American Association for Pediatric Ophthalmology and Strabismus, Vol. 14, No. 5Role of iodine in antioxidant defence in thyroid and breast diseaseBioFactors, Vol. 19, No. 3-4An elevated level of copper zinc superoxide dismutase fails to prevent oxygen induced retinopathy in mice.British Journal of Ophthalmology, Vol. 80, No. 5Rebeca Gerschman: A personal remembranceFree Radical Biology and Medicine, Vol. 21, No. 1Oxygen-induced retinopathy in the newborn rat: a scoring system for the evaluation of retinal vascular changesDocumenta Ophthalmologica, Vol. 76, No. 3The mouse model of oxygen-induced retinopathy: A suitable animal model for angiogenesis researchDocumenta Ophthalmologica, Vol. 74, No. 3Pulmonary Oxygen ToxicityRetinopathy of Prematurity and the Role of OxygenMarc Amsler, 1891-1968.British Journal of Ophthalmology, Vol. 52, No. 7BIOLOGICAL EFFECTS OF OXYGENDie retrolentale FibroplasieOxygen Studies in Retrolental Fibroplasia*American Journal of Ophthalmology, Vol. 44, No. 4Experimental Approach to the Pathogenesis of Retrolental Fibroplasia VIII. The Production of Irreversible, Severe Eye Changes through Intense and Prolonged Oxygen Exposure in MiceActa Paediatrica, Vol. 45, No. 5Experimental Approach to the Pathogenesis of Retrolental Fibroplasia VI. The Influence of the Oxygen Concentration on the Oxygen-Induced Changes in the Mouse EyeActa Paediatrica, Vol. 45, No. 3Experimental Approach to the Pathogenesis of Retrolental Fibroplasia*American Journal of Ophthalmology, Vol. 41, No. 4Experimental Approach to the Pathogenesis of Retrolental Fibroplasia. V. The Influence of the State of Nutrition on Oxygen-Induced Changes in the Mouse Eye.Acta Paediatrica, Vol. 45, No. 1Chapter I: Physical Growth30 June 2016 | Review of Educational Research, Vol. 25, No. 5Sauerstoff-IntoxikationKlinische Wochenschrift, Vol. 33, No. 19-20 More from this issue > Volume 179Issue 1October 1954Pages 115-118 Copyright & PermissionsCopyright © 1954 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1954.179.1.115PubMed13207397History Received 5 March 1954 Published online 1 October 1954 Published in print 1 October 1954 Metrics