Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma

Flor, Susanne; Oliva, Claudia R.; Ali, Md. Yousuf; Coleman, Kristen L.; Greenlee, Jeremy D.W.; Jones, Karra A.; Monga, Varun; Griguer, Corinne E.

doi:10.3390/antiox10121988

Cited by 17 publications

(18 citation statements)

References 53 publications

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“…Stable U251 and D456 cell lines ectopically expressing FLAG-tagged COX4-1 (COX4-1-U251 and COX4-1-D456, respectively) or the FLAG expression vector (vector-U251 and vector-D456, respectively) were generated as we previously described [ 15 ]. All electroporations were performed using a Gene Pulser Xcell Electroporation System (Bio Rad, Hercules, CA) as we previously described [ 15 , 73 ]. Glioma cells were electroporated with a lentiviral vector carrying one of four unique 29mer shRNA constructs specific for human COX4I1 or scramble control shRNA (OriGene Technologies, Rockville, MD; catalog # TL313764).…”

Section: Methodsmentioning

confidence: 99%

“…Lactate accumulation in the culture medium was determined using a fluorescence-based L-lactate assay kit from Cayman (Ann Arbor, MI) according to the manufacturer's instructions. Mitochondrial complex activities were determined, with results normalized to citrate synthase activity, as previously described [ 10 , 55 , 73 ].…”

Section: Methodsmentioning

confidence: 99%

“…The generation of H 2 O 2 was measured using 10 μM Amplex TM Red (ThermoFisher Scientific, Waltham, MA, USA, Cat. # A12222) as we previously described [ 73 ].…”

Section: Methodsmentioning

confidence: 99%

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COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Oliva¹,

Ali²,

Flor³

et al. 2022

CST

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Glioblastoma (GBM) is a fatal disease with recurrences often associated with radioresistance. Although often effective at treating newly diagnosed GBM, increasing evidence suggests that radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness. Using isogenic radiosensitive and radioresistant GBM cell lines and patient-derived xenolines, we found that acquired radioresistance is associated with a shift from a glycolytic metabolism to a more oxidative metabolism marked by a substantial increase in the activity of the mitochondrial res-piratory chain complex cytochrome c oxidase (CcO). This elevated CcO ac-tivity was associated with a switch in the isoform expression of the CcO regulatory subunit COX4, from COX4-2 to COX4-1, assembly of CcO-containing mitochondrial supercomplexes (SCs), and reduced superoxide (O2●-) production. Overexpression of COX4-1 in the radiosensitive cells was sufficient to promote the switch from glycolytic to oxidative metabolism and the incorporation of CcO into SCs, with a concomitant reduction in O2●- production. Conversely, silencing of COX4-1 expression in normally radiore-sistant cells reduced CcO activity, promoted the disassembly of mitochon-drial SCs, and increased O2●- production. Additionally, gain or loss of COX4-1 expression was sufficient to induce the radioresistant or radiosensitive phenotype, respectively. Our results demonstrate that COX4-1 promotes SC assembly in GBM cells, and SC assembly may in turn regulate the pro-duction of reactive oxygen species and thus the acquisition of radiore-sistance in GBM.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Oliva¹,

Ali²,

Flor³

et al. 2022

CST

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“…In addition, CAT expression is inversely associated with the survival of glioma patients. In glioma cells, CAT overexpression significantly reduces basal H 2 O 2 level and thus promotes cell growth, inducing resistance against conventional chemo-and radiotherapy [178]. Emerging evidence reveals that membrane-associated CAT imparts resistance and favors the growth of cancer cells.…”

Section: Catmentioning

confidence: 99%

Antioxidants in brain tumors: current therapeutic significance and future prospects

Jha

et al. 2022

Mol Cancer

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Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.

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“…Accumulating evidence has pointed out the potential role of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, in GBM radioresistance [ 279 ]. These enzymes have been reported to be activated up to 5-fold in a radioresistant variant clone isolated from a human U251 cell line compared to the parent cells after IR [ 279 , 280 ]. Enhanced expression of cyclooxygenase-2, also known as prostaglandin endoperoxide/H synthase 2, in GSCs has been reported to be potently involved in progressive GBM growth, as well as radioresistance [ 281 , 282 ].…”

Section: Cancer Stem Cells Concept History and Propertiesmentioning

confidence: 99%

The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance

Alhaddad

Osipov

Leonov

2022

IJMS

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Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure.

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Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma

Cited by 17 publications

References 53 publications

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Antioxidants in brain tumors: current therapeutic significance and future prospects

The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance

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