DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity
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1 Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
2 Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
3 Department of Drug Science and Technology, University of Torino, Torino, Italy
4 Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
5 CEDOC, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal, and Department of Haematology, Dumfries Royal Infirmary, Dumfries, Scotland, UK
2 Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
3 Department of Drug Science and Technology, University of Torino, Torino, Italy
4 Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
5 CEDOC, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal, and Department of Haematology, Dumfries Royal Infirmary, Dumfries, Scotland, UK
- Otan talteen lyhennykset, koska ne voivat antaa hakusanoja
Abbreviations and symbols
AA: arachidonic acid, 5, 8, 11, 14-eicosatetraenoic acid
ADHs: alcohol dehydrogenases
ALA: alpha-linolenic acid, 9, 12, 15-octadecatrienoic acid
ALDHs: Aldehyde dehydrogenases
ANA: antinuclear autoantibodies
APCs: antigen-presenting cells
AR: aldose reductase
BSA: bovine serum albumin
1, N6-ε-dAde: 1, N6-etheno-2'-deoxyadenosine
dAde: deoxyadenosine
DAMPs: damage-associated molecular patterns
DCs: dendritic cells
dCyt: deoxycytidine
ε-dCyt: 3, N4-etheno-2'-deoxycytidine
N2-dGuo: N2-propano-2'-deoxyguanosine
dGuo: deoxyguanosine
1, N2-ε-dGuo: 1, N2-etheno-2'-deoxyguanosine
dsDNA, double-strand DNA
N2, 3-ε-dGuo: N2, 3-etheno-2'-deoxyguanosine
EHN: 2, 3-epoxy-4-hydroxy-nonanal
DHA: 4, 7, 10, 13, 16, 19-docosahexanoic acid
GPX2: glutathione peroxidase 2
GAPDH: glyceraldehyde-3-phosphate dehydrogenase
GSTs: glutathione-S-transferases
HCC: hepatocellular carcinoma
HDAC: histone deacetylase
HDL3: high-density lipoprotein 3
HHE: 4-hydroxy-2(E)-hexenal
HNE: 4-hydroxy-2-nonenal
HPHE: 4-hydroperoxy-2(E)-hexenal
HPNE: 4-hydroperoxy-2(E)-nonenal
HSA: human serum albumin
HSP60: heat shock 60 kDa protein 1
HY-RNAs: histidine-rich RNAs
KLH: keyhole limpet hemocyanine
LDLs: low-density lipoproteins
LA: linoleic acid, 9, 12-octadecadienoic acid
LMP1: latent membrane protein-1
LO·: alkoxyl radical
LOO·: lipoperoxyl radical
LOX-1: oxidized low-density lipoprotein receptor 1
LOOH: lipid hydroperoxide
LPO: lipid peroxidation
mAbs: monoclonal antibodies
MDA: malondialdehyde
MSA: murine serum albumin
NAFLD: non-alcoholic fatty liver disease
NASH: non-alcoholic steatohepatitis
Nrf2: NF-E2-related factor 2
NZW: New Zealand White
8-OHdG: 8-hydroxydeoxyguanosine
·OH: hydroxyl radical
OHE: 4-oxo-2(E)-heptenal
ONE: 4-oxo-2(E)-nonenal
oxLDLs: oxidized low-density lipoproteins
OSEs: oxidation-specific epitopes
PRRs: pattern recognition receptors
PUFAs: polyunsaturated fatty acids
RA: rheumatoid arthritis
RLIP76: Ral-interacting protein
RNPs: ribonucleoprotein particles
ROS: reactive oxygen species
SCE: sister chromatide exchange
SLE: systemic lupus erythematosus
SOD2: superoxide dismutase 2
SS: Sjögren syndrome
α-CH3-γ-OH-PdG: α-hmethyl-γ-hydroxy-1, N2-propano-2'-deoxyguanosine
HNE-dGuo: 1, N2-propano-2'-deoxyguanosine adduct of HNE
9(S)-HPODE: 9(S)-hydroperoxy-9, 11-octadecadienoic acid
13(S)-HPODE: 13(S)-hydroperoxy-9, 11-octadecadienoic acid
MAP kinases: mitogen-activated protein kinases
MCL1: induced myeloid leukemia cell differentiation protein Mcl-1
M1dA: N6-(3-oxoprenyl)-deoxyadenosine
M1dC: N4-(3-oxoprenyl)-deoxycytidine
M1dG: malondialdehyde-2'-deoxyguanosine, or pyrimido[1, 2-a]purine-10(3H)-one-2'-deoxyribose
α-OH-PdG: α-hydroxy-1, N2-propano-2'-deoxyguanosine
γ-OH-PdG: γ-hydroxy-1, N2-propano-2'-deoxyguanosine
ONE-dAde: 7-(2"-oxoheptyl)-1, N6-etheno-2'-deoxyadenosine
ONE-dCyt: 7-(2"-oxoheptyl)-3, N4-etheno-2'-deoxycytidine
ONE-dGuo: 7-(2"-oxoheptyl)-1, N2-etheno-2'-deoxyguanosine
OPdG:
N2-(3-oxoprop-1-enyl)-deoxyguanosine
8-oxo-dGuo: 8-oxo-hydroxy-7, 8-dihydro-2'-deoxyguanosine
PdG:
N2-(3-oxopropyl)-deoxyguanosine
PEITC: beta-phenylethyl isothiocyanate
PPAR gamma: peroxisome proliferator-activated receptor gamma
In recent years, it has become evident that lipid peroxidation (LPO)
products are involved in the intracellular signaling mechanisms that
determine the cell's final fate [1].
LPO arises from the oxidation of fatty acids induced by oxidative
stress causing agents, e.g., oxidants, heat shock, UV and X irradiation,
metal storage, excess caloric intake and serum starvation. Oxidative
stress imports increases of reactive oxygen species (ROS) which, in
turn, can affect signaling mechanisms in a concentration-dependent
manner [2].
However, although increased ROS production has been observed in several
human diseases, such as cancer and neurodegenerative diseases, an
increase of LPO products is not always present. This is true in
particular for cancer cells, which often display high levels of
oxidative stress, whereas increased levels of LPO products were present
only in some cancer types, depending on the lipid composition of
cellular membranes, the presence of inflammation and the level of
aldehyde metabolizing enzymes [3,4].
On the contrary, in inflammatory and neurodegenerative diseases the
increases of ROS almost always were accompanied by increases of LPO and,
as a consequence, LPO products.
Several studies have been performed regarding the biological roles played by aldehydes, since they have a prolonged half-life, can diffuse from their sites of formation and react with the surrounding cells. Moreover, the aldehydes can be delivered by the bloodstream and secreted in the urine. To the contrary, free radicals, produced during LPO, have a very short life and can produce only localized effects. For these reasons, the aldehydes have been defined as "second messengers of oxidative stress" [5]. These lipid electrophiles have long been studied, due to their potential to react with nucleophilic functional groups in lipids, proteins, and DNA [6]. The nucleophilic functional groups include sulfhydryl, guanidine, imidazole and amino groups and DNA bases. In particular, the aldehydes often attack the free-NH2− groups of DNA bases to form covalent adducts, which are partially responsible for the biological consequences of LPO in normal physiology and pathophysiology. In this review we summarize the most recent evidence of DNA damage by LPO products in several diseases, such as cancer, inflammation and autoimmunity.
Several studies have been performed regarding the biological roles played by aldehydes, since they have a prolonged half-life, can diffuse from their sites of formation and react with the surrounding cells. Moreover, the aldehydes can be delivered by the bloodstream and secreted in the urine. To the contrary, free radicals, produced during LPO, have a very short life and can produce only localized effects. For these reasons, the aldehydes have been defined as "second messengers of oxidative stress" [5]. These lipid electrophiles have long been studied, due to their potential to react with nucleophilic functional groups in lipids, proteins, and DNA [6]. The nucleophilic functional groups include sulfhydryl, guanidine, imidazole and amino groups and DNA bases. In particular, the aldehydes often attack the free-NH2− groups of DNA bases to form covalent adducts, which are partially responsible for the biological consequences of LPO in normal physiology and pathophysiology. In this review we summarize the most recent evidence of DNA damage by LPO products in several diseases, such as cancer, inflammation and autoimmunity.
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