Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?

Abstract

The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and growth or causing cell death. Cells developed evolutionarily conserved programs to sense and adapt redox the fluctuations to regulate ROS as either signaling molecules or toxic insults. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2)-KEAP1 system is the master regulator of cellular redox and metabolic homeostasis. NRF2 has Janus-like roles in carcinogenesis and cancer development. Short-term NRF2 activation suppresses tissue injury, inflammation, and cancer initiation. However, cancer cells often exhibit constitutive NRF2 activation due to genetic mutations or oncogenic signaling, conferring advantages for cancer cells’ survival and growth. Emerging evidence suggests that NRF2 hyperactivation, as an adaptive cancer phenotype under stressful tumor environments, regulates all hallmarks of cancer. In this review, we summarized the source of ROS, regulation of ROS signaling, and cellular sensors for ROS and oxygen (O2), we reviewed recent progress on the regulation of ROS generation and NRF2 signaling with a focus on the new functions of NRF2 in cancer development that reach beyond what we originally envisioned, including regulation of cancer metabolism, autophagy, macropinocytosis, unfolded protein response, proteostasis, and circadian rhythm, which, together with anti-oxidant and drug detoxification enzymes, contributes to cancer development, metastasis, and anticancer therapy resistance.

Molecular Mechanisms of Oxidative Stress in Acute Kidney Injury: Targeting the Loci by Resveratrol

“…The O 2 − generated in the mitochondria reacts with mnSOD in the mitochondrial matrix to produce H 2 O 2 , which in turn can cross the mitochondrial outer membrane and reach the cytosolic targets. The H 2 O 2 assault on the cytosolic targets can cause numerous deleterious functional consequences such as stimulation of redox-sensitive transcription factors, proinflammatory cytokines, and inflammasomes [ 101 , 102 , 103 ]. mtROS can also contribute to increased oxidative stress through interactions with NOS [ 87 ].…”

Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo

“…Upon exposure to sunlight, endogenous chromophores present in the skin initiate the conversion of sunlight photons to ROS. Although ROS have important physiological functions in cell signaling, enzymatic reactions, and resistance against microbes, their excessive levels can be toxic unless they are removed in a timely manner ( Wang et al ., 2023 ). As keratinocytes form the outermost layer of the skin and are frequently exposed to stressful stimuli, sophisticated cyto-protective functions likely play an important role in maintaining their proper functions in this tissue.…”

Characterization of tRNA-Derived Fragments in Lung Squamous Cell Carcinoma with Respect to Tobacco Smoke

“…A wide range of evidence has proved that tobacco smoke contains over 3500 chemicals and 60 carcinogens, which include but are not limited to volatile organic hydrocarbons, polycyclic aromatic hydrocarbons, and N -Nitrosamines [ 17 ]. Moreover, some of the chemicals in tobacco smoke are considered to be reactive oxygen species (ROS), which can promote inflammation and mediate processes such as cell proliferation, cell cycle progression, and metastasis [ 17 , 18 ]. Accordingly, data have demonstrated that the byproducts of the chemicals and compounds in tobacco smoke are found in the urine of smokers at higher levels than that of non-smokers.…”