Reactive oxygen species in cancer: Current findings and future directions

Abstract

Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared with normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment.

Keywords: cell death; neoplasms; oxidative stress; reactive oxygen species; therapeutics.

FIGURE 1

Generation of reactive oxygen species (ROS) and their effects. Reactive oxygen species can be generated by multiple endogenous and exogenous factors, which, in turn, lead to various biological consequences. Low levels of ROS act as intracellular second messengers. Moderate levels of ROS are beneficial to cancer cells because they can increase cancer metabolism and growth signaling, and inhibit antioxidants, which contribute to oncogenesis. Conversely, high levels of ROS can lead to cell death induced by DNA damage

FIGURE 2

Schematic representation of STEAP1‐NRF2 pathway. Under nonoxidative conditions, nuclear erythroid 2‐related factor (NRF2) is located in the cytoplasm, adjacent to kelch‐like ECH‐associated protein 1 (KEAP1). Oxidative stress causes the dissociation of NRF2 from KEAP1. NRF2 enters the nucleus and activates several cytoprotective genes for protection against oxidative stress. Our previous report suggested that six‐transmembrane epithelial antigen of the prostate 1 (STEAP1) plays an important role in upregulating this pathway. ARE, antioxidant response element

FIGURE 3

Iron overload leads to ROS and 8‐oxodG. Reactive oxygen species (ROS) can be induced by iron and contribute to the formation of mutagenic 8‐oxo‐7‐hydro‐2′‐deoxyguanosine (8‐oxodG), which leads to hepatocarcinogenesis (HCC) in patients with chronic hepatitis C (CHC)/non‐alcoholic steatohepatitis (NASH), and leukemic transformation in myelodysplastic syndrome (MDS). Therapeutic iron reduction contributes to inhibiting both hepatocarcinogenesis in CHC/NASH and leukemic transformation in MDS

FIGURE 4

Schematic representation of cell death induced by ROS. A, Reactive oxygen species (ROS) can lead to activation of apoptosis. High levels of mitochondrial ROS can release cytochrome c into the cytosol from the mitochondrial intermembrane space. In the cytosol, cytochrome c engages apoptotic protease activating factor‐1 (APAF1) and activates caspase‐9. Furthermore, as the extrinsic pathway, ROS can activate transmembrane death receptors, including Fas, tumor necrosis factor‐related apoptosis inducing ligand (TRAIL‐R1/2), Fas‐associated protein with death domain (FADD), and procaspase‐8 and ‐10 at the cytoplasmic surface to form death‐inducing signaling complexes (DISCs), subsequently triggering caspase‐8 and ‐10 activation, and apoptosis. Caspase‐8 and ‐10 also cleave Bid to produce truncated (t)Bid, which translocates to mitochondria, blocks Bcl‐2 and Bcl‐XL, and activates Bax and Bak. B, ROS can regulate autophagy induction in cells. Increased ROS leads to oxidation and inactivation of autophagy‐related (ATG)4. Inactivation of ATG4 results in promoting lipidation of ATG8, an essential step in autophagy. ROS also directly activate adenosine monophosphate (AMP)‐activated protein kinase (AMPK), upstream of mammalian target of rapamycin (mTOR), to suppress its phosphorylation, resulting in the induction of autophagy