Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Pannala, Venkat R.; Dash, Ranjan K.

doi:10.1016/j.freeradbiomed.2014.10.508

Cited by 57 publications

(41 citation statements)

References 61 publications

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“…For example, there are studies of the Warburg effect, including modeling of the regulation by reactive oxygen species (ROS) of hypoxia-inducible factor 1 (HIF-1) in response to hypoxia (22), and modeling of the genome-scale metabolic network based on metabolic flux balance analysis (23). Some other studies focused on mitochondrial functions, for example, in the study of the cooperative effects of TrxR and Prx in defending oxidative stresses (24). The evolutionary advantage of metabolic heterogeneity of cancer has also been investigated (25) with emphasis on glycolysis and acidity.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

et al. 2017

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Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. Integrating information from literature, we constructed a regulatory network of genes and metabolites from which we extracted a core circuit containing HIF-1, AMPK, and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access a hybrid state with both metabolic modes coexisting. This was due to higher ROS production and/or oncogene activation, such as RAS, MYC, and c-SRC. Guided by the model, we developed two signatures consisting of AMPK and HIF-1 downstream genes, respectively, to quantify the activity of glycolysis and OXPHOS. By applying the AMPK and HIF-1 signatures to TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anti-correlation between AMPK and HIF-1 activities and the association of metabolic states with oncogenes. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism.

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Section: Introductionmentioning

confidence: 99%

Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

et al. 2017

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“…The present data revealed a significant increase in PRDX2 in liver of hibernating squirrels and an increase in TRX1, the reducing partner of PRDX [33]. A parallel study performed in our lab found unchanged levels of PRDX2 in BAT and WAT, but a significant increase was noted in TRX1 during torpor [42].…”

Section: Discussionsupporting

confidence: 76%

“…Mammalian cells possess two TRX systems -cytosolic TRX1 and mitochondrial TRX2where TRX2 has only two cysteines in its active site, whereas TRX1 has three additional cysteines [32]. TRX provides electrons to thiol-dependent PRDXs to break down H2O2 in a ping-pong mechanism [33]. PRDXs are a ubiquitous family of antioxidant proteins with 6 different isoforms that use specialized cysteine residues to break down hydroperoxides.…”

Section: Antioxidant Enzymesmentioning

confidence: 99%

Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

Szereszewski¹

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Hibernation is a fascinating survival adaptation that allows animals to transition into a torpid state to survive the winter by coordinating a strong suppression of metabolic rate, conservation of fuel/energy, and reduction of body temperature. This strategy permits thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and other hibernating mammals to endure the harsh winter season when there is little access to food. Many energy-expensive cellular processes are suppressed, including gene transcription and protein synthesis/turnover, but are reactivated rapidly when animals arouse back to euthermia. Both torpor and arousal can have damaging consequences; for example, during arousal, reactive oxygen species flood the cell causing oxidative damage to numerous cellular components. Therefore, hibernation requires many pro-survival mechanisms to mitigate multiple types of damage: e.g. from oxidative damage, DNA damage, and pathogen attack, among others. The research reported in this thesis on damage control processes in hibernators shows that antioxidant enzymes such as PRDXs are upregulated in key tissues but in an isoform-specific and time-specific manner over the torpor-arousal cycle. PRDX2, 3, 4 and 6 were found to be significantly upregulated in specific tissues.Similarly, DNA damage repair is initiated during torpor and is characterized by the binding of repair proteins such as Ku80 and the MRN complex to the site of breaks, but ligation (with XLF) reactions to fully repair DNA do not appear to occur until the arousal period.Pro-inflammatory mechanisms are also used to deal with pathogens; these remain active at basal levels in a tissue-specific manner during torpor, but are up-regulated in the final stages just before arousal or only during arousal depending on the tissue, such as the induction of CCL5, a recruiter of monocytes. A cyto/neuro-protective mitochondrial peptide, shumanin, was also identified that is induced in a tissue-specific manner, helping to protect key organs such as the brain cortex and adipose tissues. The results show that hibernation is a complex, multi-faceted process that employs specific adaptations of damage prevention/repair pathways to protect squirrel tissues from damage not only during prolonged torpor but over the transitional states to/from torpor and does so expertly while conserving energy until such a time that repair mechanisms may be fully initiated.iv

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“…Tpx is essential for converting H 2 O 2 (reactive) to H 2 O (harmless) (Pannala and Dash, 2015), and RNR for converting ribonucleoside 5′-diphosphates species (ADP, UDP, GDP and CDP), to deoxy-species (dADP, dUDP, dGDP and dCDP) which are used for DNA synthesis (Munro and Silva, 2012). …”

Section: Discussionmentioning

confidence: 99%

Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

Tewari

Prigge

Reifman

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Chloroquine, long the default first-line treatment against malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient drug, a coherent understanding of the cellular mechanisms affected by chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome-scale transcriptomics to map out the effects of chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both drug-sensitive and drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced thioredoxin and phosphoenolpyruvate synthesis are significantly decreased and are pivotal to chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of chloroquine (or an analogue) and another drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P. falciparum from the host system.

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Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Cited by 57 publications

References 61 publications

Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

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