Lipid peroxidation: Reactive carbonyl species, protein/DNA adducts, and signaling switches in oxidative stress and cancer

Under the exposure of lipids to reactive oxygen species (ROS), lipid peroxidation proceeds non-enzymatically and generates an extremely heterogeneous mixture of reactive carbonyl species (RCS). Among them, HNE, HHE, MDA, methylglyoxal, glyoxal, and acrolein are the most studied and/or abundant ones. Over the last decades, significant progress has been achieved in understanding mechanisms of RCS generation, protein/DNA adduct formation, and their identification and quantification in biological samples. In our review, we critically discuss the advancements in understanding the roles of RCS-induced protein/DNA modifications in signaling switches to provide adaptive cell response under physiological and oxidative stress conditions. At non-toxic concentrations, RCS modify susceptible Cys residue in c-Src to activate MAPK signaling and Cys, Lys, and His residues in PTEN to cause its reversible inactivation, thereby stimulating PI3K/PKB(Akt) pathway. RCS toxic concentrations cause irreversible Cys modifications in Keap1 and IKK beta followed by stabilization of Nrf2 and activation of NF-kappa B, respectively, for their nuclear translocation and antioxidant gene expression. Dysregulation of these mechanisms causes diseases including cancer. Alterations in RCS, RCS detoxifying enzymes, RCSmodified protein/DNA adducts, and signaling pathways have been implicated in various cancer types.

Automated summary

This study reviews the advancements in understanding the generation of reactive carbonyl species (RCS), the formation of protein/DNA adducts, and their identification and quantification in biological samples. It reveals that at certain concentrations, RCS can activate specific signaling pathways through the modification of susceptible residues, but at toxic concentrations, irreversible modification of Cys residues occurs, leading to the development of diseases.