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Metabolic Regulation of Redox Balance in Cancer.

ABSTRACT: Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis.

SUBMITTER: Purohit V

PROVIDER: S-EPMC6678865 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Metabolic Regulation of Redox Balance in Cancer.

Purohit Vinee V Simeone Diane M DM Lyssiotis Costas A CA

Cancers 20190708 7

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, addit ...[more]

PMID: 31288436

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Project description:BACKGROUND:Scheffersomyces stipitis is an important yeast species in the field of biorenewables due to its desired capacity for xylose utilization. It has been recognized that redox balance plays a critical role in S. stipitis due to the different cofactor preferences in xylose assimilation pathway. However, there has not been any systems level understanding on how the shift in redox balance contributes to the overall metabolic shift in S. stipitis to cope with reduced oxygen uptake. Genome-scale metabolic network models (GEMs) offer the opportunity to gain such systems level understanding; however, currently the two published GEMs for S. stipitis cannot be used for this purpose, as neither of them is able to capture the strain's fermentative metabolism reasonably well due to their poor prediction of xylitol production, a key by-product under oxygen limited conditions. RESULTS:A system identification-based (SID-based) framework that we previously developed for GEM validation is expanded and applied to refine a published GEM for S. stipitis, iBB814. After the modified GEM, named iDH814, was validated using literature data, it is used to obtain genome-scale understanding on how redox cofactor shifts when cells respond to reduced oxygen supply. The SID-based framework for GEM analysis was applied to examine how the environmental perturbation (i.e., reduced oxygen supply) propagates through the metabolic network, and key reactions that contribute to the shifts of redox and metabolic state were identified. Finally, the findings obtained through GEM analysis were validated using transcriptomic data. CONCLUSIONS:iDH814, the modified model, was shown to offer significantly improved performance in terms of matching available experimental results and better capturing available knowledge on the organism. More importantly, our analysis based on iDH814 provides the first genome-scale understanding on how redox balance in S. stipitis was shifted as a result of reduced oxygen supply. The systems level analysis identified the key contributors to the overall metabolic state shift, which were validated using transcriptomic data. The analysis confirmed that S. stipitis uses a concerted approach to cope with the stress associated with reduced oxygen supply, and the shift of reducing power from NADPH to NADH seems to be the center theme that directs the overall shift in metabolic states.

Dataset Information

Metabolic Regulation of Redox Balance in Cancer.

Publications

Metabolic Regulation of Redox Balance in Cancer.

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