Reactive Oxygen Species: A Key Constituent in Cancer Survival

Abstract

Background: Cancer is one of the major heterogeneous disease with high morbidity and mortality with poor prognosis. Elevated levels of reactive oxygen species (ROS), alteration in redox balance, and deregulated redox signaling are common hallmarks of cancer progression and resistance to treatment. Mitochondria contribute mainly in the generation of ROS during oxidative phosphorylation. Elevated levels of ROS have been detected in cancers cells due to high metabolic activity, cellular signaling, peroxisomal activity, mitochondrial dysfunction, activation of oncogene, and increased enzymatic activity of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphorylases. Cells maintain intracellular homeostasis by developing an immense antioxidant system including catalase, superoxide dismutase, and glutathione peroxidase. Besides these enzymes exist an important antioxidant glutathione and transcription factor Nrf2 which contribute in balancing oxidative stress. Reactive oxygen species-mediated signaling pathways activate pro-oncogenic signaling which eases in cancer progression, angiogenesis, and survival. Concomitantly, to maintain ROS homeostasis and evade cancer cell death, an increased level of antioxidant capacity is associated with cancer cells.

Conclusions: This review focuses the role of ROS in cancer survival pathways and importance of targeting the ROS signal involved in cancer development, which is a new strategy in cancer treatment.

Keywords: MMPs; Nrf2; ROS; cancer survival.

Figure 1.

Mitochondrial generation of ROS. The electrons generated from the metabolic intermediates lead to the production of ROS at specific location in the mitochondria (mtROS or mROS). The generation of the ROS mainly takes place during the process of oxidative phosphorylation at the ETC located on the inner mitochondrial membrane. Complexes I, II, and III play a pivotal role in the generation of ROS. Release of electrons at complexes I and III from electron transport chains leads to partial reduction of oxygen to form a free radical such as superoxide. Superoxide is released to the intermembrane space from complex III, owing to generation from ubisemiquinone at the outer ubiquinone-binding site (Qo) of complex III. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by 2 dismutases including superoxide dismutase 2 (SOD2). The H₂O₂ is degraded in the matrix by glutathione peroxidase (GPx). ETC indicates electron transport chain; ROS, reactive oxygen species.

Figure 2.

Role of ROS in signal transduction. ROS induce activation of PI3K/AKT/mTOR survival signaling leads to the activation of mainly 2 signaling pathways: Ras-MAPK, which results in cell proliferation, and PI3K-Akt-eNOS, which results in metabolic modulation and cell survival. Hypoxia causes the activation of HIFα-HIFβ, which further activates VEGF, an angiogenic growth factor. In cancer cell ROS, high concentration of ROS activates survival pathway and inactivates PTEN pathway which initiates apoptosis. ROS indicate reactive oxygen species; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor.

Figure 3.

Immune evasion of ROS through antioxidant defense in cancer survival. (A) H₂O₂ generated in the matrix can oxidize biomolecules including proteins, lipid membrane, and DNA-generating alkoxy radical by Fenton reaction. H₂O₂ generated can be converted to HO₂ by catalase, glutathione peroxidase. Glutathione exists in reduced form as GSH in the enzyme glutathione peroxidase and gets oxidized (GSSG) in the process of reduction of H₂O₂. Oxidized glutathione (GSSG) is reduced by glutathione reductase, which obtains its equivalents NADPH from HMP shunt. (B) Nrf2-ARE pathway activation takes place when cell is subjected to oxidative stress. In the cytoplasm, Nrf2 is constitutively bound to Keap1 form in the form of dimer—Nrf2-Keap1. During oxidative stress, Nrf2 is released from Keap1, hence allowing the transcriptional factor Nrf2 to translocate to the nucleus. Nrf2 in MAF family proteins binds with ARE-regulated genes. This activates antioxidant enzymes, pro-inflammatory response, and cell survival. ARE indicates antioxidant responsive element; HMP, hexose monophosphate; ROS, reactive oxygen species.

Figure 4.

Overview of ROS in cancer progression and specific target in cancer therapy. ROS indicate reactive oxygen species.