Abstract
Manipulative strategies of ROS in cancer are often exhibited as changes in the redox and thiol ratio of the cells. Cellular responses to oxidative insults are generated in response to these changes which are triggered due to the rerouting of the metabolic framework to maintain survival under stress. However, mechanisms of these metabolic re-routing are not clearly understood and remained debatable. In the present work, we have designed a context-based dynamic metabolic model to establish that the coordinated functioning of glutathione peroxidase (GTHP), glutathione oxidoreductase (GTHO) and NADPH oxidase (NOX) is crucial in determining cancerous transformation, specifically in gliomas. Further, we propose that the puzzling duality of ROS (represented by changes in h2o2 in the present model) in exhibiting varying cellular fates can be determined by considering simultaneous changes in nadph/nadp+ and gsh/gssg that occur during the reprogramming of metabolic reactions. This will be helpful in determining the pro-apoptotic or anti-apoptotic fate of gliomas and can be useful in designing effective pro-oxidant and/or anti-oxidant therapeutic approaches against gliomas.
Highlights
Reactive Oxygen Species (ROS) have been implicated in various disease conditions and are considered as a key driving factor in the process of aging and carcinogenesis
ROS which typically show a paradoxical behavior in tumor progression and proliferation have been represented in the model with the inclusion of ROS production machinery. gsh is a tri-peptide composed of cystine, glycine and glutamate, is the prime anti-oxidant involved in ROS scavenging
The gsh-gssg cycle consisting of glutathione peroxidase (GTHP) and glutathione oxidoreductase (GTHO) has been included along with the ROS production machinery comprising of NADPH Oxidase (NOX) and Superoxide Dismutase (SOD)
Summary
Reactive Oxygen Species (ROS) have been implicated in various disease conditions and are considered as a key driving factor in the process of aging and carcinogenesis. ROS is referred to possess a double-edged sword property having both tumor-promoting and a tumor-suppressing function [1]. An intricate balance between ROS and antioxidants and other ROS scavengers is maintained in a normal proliferating cell, which is a prerequisite for maintaining redox balance and proper functioning of the cell. Human cells generally tend to function in a reduced state (e.g. by maintaining high gsh/gssg ratio [2] and high nadph/nadp+ ratio [3]). Exceptions are made when the cells need to maintain a slightly oxidative environment to aid various cellular processes like folding of nascent proteins in the endoplasmic reticulum, activation of gene transcription factors, etc.
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