It has beendemonstrated that in cancer cells: at low levels of ROS, they act as signaling molecules toactivate proliferation and survival pathways. A moderate increase in ROS levelsis caused because of genetic, metabolic and microenvironment-associatedalteration. This leads to DNA damage and promotes mutagenesis in cells. HighROS levels causes oxidative stress that can lately result in cell senescence ordeath.
It is known to cause cell toxicity. Intracellular ROSaccumulation is associated to high toxicity at cellular and tissue levels andit is responsible of oxidative stress and harm in biomolecules such as lipids,proteins and nucleic acids. Due to this fact, it is necessary to eradicate theadditional ROS, avoiding it´s negative consequences.
Aerobic organismsmentioned before, own enzymatic mechanisms to remove in an efficient way thisadditional ROS, by generating H2O and O2. By doing this, we canavoid the extra ROS accumulation in cells. Once tumors are established, tumor propagating cancer stem cells (TPCs) must reduce ROS levels, to sustain their long-term self-renewing capacity and to avoid their differentiation.
To prevent excessive oxidative stress, tumor cellsadjust antioxidant enzymes using their metabolic pathway to provide an adequatesupply of antioxidant molecules. The most relevant antioxidant enzymes within the cells isglutathione (GSH) which uses glutathione peroxidases that eliminate H2O2to H2O. Another important defensive mechanism is the one known asThioredoxin. Superoxide dismutases (SODs) that convert superoxide O2-to less reactive H2O2. For countering the impactof ROS species, cells develop antioxidant response strategies.
Nuclear factor erythroid2-related factor 2 (NRF2) signaling pathway is one of the pathways that hasbeen very well studied. NRF2 is a transcription factor known as the masterregulator of the antioxidant response in cancer. It is induced by ROS and can regulatethe expression of enzymes that control NADPH production, the glutathionesynthesis, detoxification of glutathione production as well as the mechanismthat reduces the proteins that are oxidized by ROS species. Still, how Nrf2 and target gene transcription are controlled in TPCs remains elusive. Some of the genes regulated by NRF2 are: