ROS Elimination Redox homeostasis is regulated by the antioxidant enzymes. (ROS), as second messengers, function in various cellular signal pathways in normal cells and cancer cells [1]. Redox homeostasis is regulated by a balanced status between ROS production and scavenging (Figure 1) [1,2]. Signal cascades induced by stimuli can lead to ROS generation from ligand-receptor interactions [2,3,4]. Molecules that can directly penetrate the cell membrane, such as lipophilic growth hormones (steroid hormones and thyroid hormones) and chemical drugs, can activate mitochondrial-mediated ROS generation [5,6,7]. Although various stimuli can induce changes in ROS and affect the physiological response in cells, the antioxidant proteins stabilize ROS levels to maintain redox homeostasis [8]. Superoxide dismutase (SOD), catalase, peroxiredoxin (Prx), and nuclear factor erythroid 2-related factor 2 (Nrf2) are antioxidant modules [9]. Local ROS level, as a second messenger, amplifies only the specific region where receptor activation transduces a linear signal response. [3,10]. This process is regulated locally by ROS inducers and antioxidant modules to overcome the possibility that the alternative ROS can affect whole cells [3]. Open in a separate window Figure 1 Redox homeostasis between generation and elimination of reactive oxygen species (ROS). ROS production is regulated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) in membranes, the electron transport chain (ETC) of the adenosine triphosphate (ATP) synthesis process in mitochondria, and the protein synthesis process in endoplasmic reticulum (ER) during O2 consumption. Alternative levels of ROS induce DNA damage or transcription factors (TFs)-mediated gene expression in the nucleus. The superoxide anion (O2??) produced intracellularly is neutralized to hydrogen peroxide (H2O2) by the superoxide dismutase (SOD) family. H2O2 are detoxified to H2O by catalase and peroxiredoxin (Prx). ROS regulate cellular processes such as proliferation, apoptosis, chemoresistance, and differentiation through a variety of signaling pathways. Many Polidocanol studies have shown that redox imbalances can induce signaling pathways that promote cancer progression, senescence, differentiation, and apoptosis [8]. Cancer Polidocanol cells show enhanced glycolysis-mediated metabolisms to overcome over-utilized ATP or alter cellular signal pathways [11]. Thus, many SLC2A4 cancer cells upregulate antioxidants as protection against their high levels of ROS. Chemotherapeutic agents can induce increased ROS levels, and most cancer cells treated with chemotherapy suffer from ROS-mediated apoptosis [12]. Some cancer cells evolve mechanisms to escape ROS-mediated apoptosis and acquire tolerance to anti-cancer drugs [13]. The ROS system has a dual function that can either induce apoptosis or allow cells to adapt to various environments. ROS regulation has thus been a critical target for the development of anticancer drugs [14]. In this review, we discuss the change of redox balance by the generation or removal of ROS in tumorigenesis and redox-mediated mechanisms of the chemoresistance in chemotherapy. 2. Redox Homeostasis in Tumorigenesis 2.1. ROS Generation Intracellular redox functions as an oncogenic factor for the activation of signal transduction in tumorigenesis [9]. ROS consists of both free radical and non-radical groups. The free radical group includes superoxide anion (O2??), peroxyl radical (RO2?), hydroxyl radical (?OH), and hydroperoxyl radical (HO2?). Hydrogen peroxide (H2O2) and single oxygen (1O2) are classified as non-radical ROS. Production of intracellular ROS is generated by ATP synthesis in mitochondria, protein synthesis in the endoplasmic reticulum (ER), and activation of (NADPH) oxidase NOX family members [5]. 2.1.1. ATP Synthesis in Mitochondria Mitochondria generate intracellular ROS during the electron transport chain (ETC) of the ATP synthesis process [15]. The homeostasis of ROS in mitochondria is maintained by antioxidant proteins. Upon electron leakage of the ETC, the abnormal ROS status of mitochondria can activate apoptosis in carcinoma cells [15,16]. Cancer cells show increased metabolism for Polidocanol their elevated proliferation and migration. Cancer cells have significantly increased the ATP production as well as the ROS [15,16,17,18]. Chemoresistant cancer cells require the active pump of the ATP-driven multidrug efflux, such as ATP-binding cassette (ABC) transporters [19]. The role of these transporters is to pump out intracellular toxic chemical drugs into the extracellular region by ATP hydrolysis [20]. ABC transporters include multidrug resistance-associated protein 1 (MRP1/ABCC1), breast cancer resistance protein/ABC subfamily G member 2 (BCRP/ABCG2), ABC subfamily B member 5 (ABCB5), and multidrug resistance protein 1/ABC subfamily B member 1 (MDR1/ABCB1) [19,20,21]. Enhanced ROS level is generated by the ETC, but the antioxidant machinery is induced to adapt to the bigger ROS also.
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