Aldehydes Derived from Lipid Peroxidation in Cancer and Autoimmunity

The unsaturated aldehydes derived from lipid peroxidation (LPO), such as 4- hydroxy-2-nonenal (HNE), which are characterized by high chemical reactivity, diffusibility, and relatively long life, are considered to act as second messengers of oxidative stress. The majority of the cellular effects of reactive aldehydes are mediated by their interactions with either low-molecular-weight compounds, such as glutathione, or macromolecules, as proteins and DNA. In particular, aldehyde-protein adducts have been extensively investigated in disease conditions characterized by the pathogenic contribution of oxidative stress, such as cancer and autoimmune diseases. In cancer, these aldehydes can act as either positive or negative regulators, depending on their concentration and the tissue considered. As a consequence, the role of reactive aldehydes in cancer is double-sided. The ‘dark-side’ of reactive aldehydes has to do with their carcinogenic potential, while they also display anti-cancer effects, such as the inhibition of cell proliferation, angiogenesis, cell adhesion and the induction of differentiation and/or apoptosis in various tumor cell lines. The modification of self antigens via the formation of adducts of unsaturated aldehydes, such as HNE, is also linked to the breaking of immunological tolerance to self antigens in various autoimmune diseases. In experimental mice, T cell sensitization to HNE-modified autoantigens, such as SS-A2/Ro60, a prominent autoantigenic target of antinuclear autoantibodies in systemic lupus erythematosus (SLE) and Sjögren syndrome (SS), promoted the intramolecular spreading of the immune response to formerly tolerated epitopes of the native self antigen and the intermolecular spreading to other protein antigens and to DNA. Further investigations of the molecular mimicry between the adducts of HNE and its analog 4-oxo-2-nonenal (ONE) with proteins and DNA and of the specificity of antibodies found in mice immunized with HNE-modified proteins and in patients with SLE suggest that HNE-containing neoepitopes formed upon HNE generation and reaction with cell proteins can be instrumental for the breaking of immunological tolerance to self protein antigens and for the production of bispecific autoantibodies, cross-reacting with native and aldehyde-modified DNA.