4-hydroxy-2-nonenal and Carcinogenesis

4-hydroxy-2-nonenal (HNE) is an amazing reactive compound, originating from lipid peroxidation within cells but also in food and considered as a "second messenger" of oxidative stress. Due to its chemical features, HNE is able to make covalent links with DNA, proteins and lipids. The aim of this review is to give a comprehensive summary of the chemical properties of HNE and of the consequences of its reactivity in relation to cancer development. The formation of exocyclic etheno-and propano-adducts and genotoxic effects are addressed. The adduction to cellular proteins and the repercussions on the regulation of cell signaling pathways involved in cancer development are reviewed, notably on the Nrf2/Keap1/ARE pathway. The metabolic pathways leading to the inactivation/elimination or, on the contrary, to the bioactivation of HNE are considered. A special focus is given on the link between HNE and colorectal cancer development, due to its occurrence in foodstuffs and in the digestive lumen, during digestion.

Topics: Aldehydes; Carcinogenesis; Colon; Colorectal Neoplasms; DNA Adducts; Gene Expression Regulation, Neoplastic; Humans; Inflammatory Bowel Diseases; Kelch-Like ECH-Associated Protein 1; Mitogen-Activated Protein Kinases; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Precancerous Conditions; Protein Kinase C; Signal Transduction

Consistent experimental data suggest the importance of inflammation-associated oxidative stress in colorectal cancer (CRC) pathogenesis. Inflammatory bowel disease with chronic intestinal inflammation is now considered a precancerous condition. Oxidative stress is an essential feature of inflammation. Activation of redox-sensitive pro-inflammatory cell signals and inflammatory mediators concur to establish a pro-tumoral environment. In this frame, lipid oxidation products, namely 4-hydroxynonenal and oxysterols, can be produced in big quantity so as to be able to exert their function as inducers of cell signaling pathways of proliferation and survival. Notably, an important source of these two compounds is represented by a high fat diet, which is undoubtedly a risk factor for inflammation and CRC development. Current evidence for the emerging implication of these two oxidized lipids in inflammation and CRC development is discussed in this review.

Topics: Aldehydes; Carcinogenesis; Cholesterol; Colon; Colorectal Neoplasms; Diet, High-Fat; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Inflammatory Bowel Diseases; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Oxysterols; Risk Factors; Signal Transduction; STAT3 Transcription Factor

While reactive oxygen species (ROS) gain their carcinogenic effects by DNA mutations, if generated in the vicinity of genome, lipid peroxidation products, notably 4-hydroxynonenal (HNE), have much more complex modes of activities. Namely, while ROS are short living and have short efficiency distance range (in nm or µm) HNE has strong binding affinity for proteins, thus forming relatively stable adducts. Hence, HNE can diffuse from the site or origin changing structure and function of respective proteins. Consequently HNE can influence proliferation, differentiation and apoptosis of cancer cells on one hand, while on the other it can affect genome functionality, too. Although HNE is considered to be important factor of carcinogenesis due to its ability to covalently bind to DNA, it might also be cytotoxic for cancer cells, as well as it can modulate their growth. In addition to direct cytotoxicity, HNE is also involved in activity mechanisms by which several cytostatic drugs and radiotherapy exhibit their anticancer effects. Complementary to that, the metabolic pathway for HNE detoxification through RLIP76, which is enhanced in cancer, may be a target for anti-cancer treatments. In addition, some cancer cells can undergo apoptosis or necrosis, if exposed to supraphysiological HNE levels in the cancer microenvironment, especially if challenged additionally by pro-oxidative cytostatics and/or inflammation. These findings could explain previously observed disappearance of HNE from invading cancer cells, which is associated with the increase of HNE in non-malignant cells close to invading cancer utilizing cardiolipin as the source of cancer-inhibiting HNE.

Topics: Aldehydes; ATP-Binding Cassette Transporters; Carcinogenesis; Cardiolipins; Cell Proliferation; Gene Expression Regulation, Neoplastic; GTPase-Activating Proteins; Humans; Neoplasms; NF-E2-Related Factor 2; NF-kappa B; Oxidation-Reduction; Protein Kinase C; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Suppressor Protein p53

An oxidative degradation product of the polyunsaturated fatty acids, 4-hydroxynonenal (4-HNE), is of particular interest in cancer research due to its concentration-dependent pleiotropic activities affecting cellular antioxidants, metabolism, and growth control. Although an increase in oxidative stress and lipid peroxidation was already associated with prostate cancer progression a few decades ago, the knowledge of the involvement of 4-HNE in prostate cancer tumorigenesis is limited. This study investigated the appearance of 4-HNE-protein adducts in prostate cancer tissue by immunohistochemistry using a genuine 4-HNE monoclonal antibody. Plasma samples of the same patients and samples of the healthy controls were also analyzed for the presence of 4-HNE-protein adducts, followed by metabolic profiling using LC-ESI-QTOF-MS and GC-EI-Q-MS. Finally, the analysis of the metabolic pathways affected by 4-HNE was performed. The obtained results revealed the absence of 4-HNE-protein adducts in prostate carcinoma tissue but increased 4-HNE-protein levels in the plasma of these patients. Metabolomics revealed a positive association of different long-chain and medium-chain fatty acids with the presence of prostate cancer. Furthermore, while linoleic acid positively correlated with the levels of 4-HNE-protein adducts in the blood of healthy men, no correlation was obtained for cancer patients indicating altered lipid metabolism in this case. The metabolic pathway of unsaturated fatty acids biosynthesis emerged as significantly affected by 4-HNE. Overall, this is the first study linking 4-HNE adduction to plasma proteins with specific alterations in the plasma metabolome of prostate cancer patients. This study revealed that increased 4-HNE plasma protein adducts could modulate the unsaturated fatty acids biosynthesis pathway. It is yet to be determined if this is a direct result of 4-HNE or whether they are produced by the same underlying mechanisms. Further mechanistic studies are needed to grasp the biological significance of the observed changes in prostate cancer tumorigenesis.

Topics: Aldehydes; Biomarkers; Carcinogenesis; Fatty Acids, Unsaturated; Humans; Lipid Peroxidation; Male; Prostatic Neoplasms; Proteins

Topics: Aldehydes; Animals; Carcinogenesis; DNA Damage; Female; Humans; Melanoma; Metformin; Mice; Oxidative Stress; Radiation Injuries, Experimental; Radiodermatitis; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Tyrosine; Ultraviolet Rays