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The role of the cellular antioxidant defense in oxidant carcinogenesis
1Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Epalinges/Lausanne.
Abstract:
Oxidant carcinogens interact with multiple cellular targets including membranes, proteins, and nucleic acids. They cause structural damage to DNA and have the potential to mutate cancer-related genes. At the same time, oxidants activate signal transduction pathways and alter the expression of growth- and differentiation-related genes. Indeed, the carcinogenic action of oxidants results from the superposition of these genetic and epigenetic effects. All cells possess elaborate antioxidant defense systems that consist of interacting low and high molecular weight components. Among them, superoxide dismutases (SOD), glutathione peroxidases (GPx), and catalase (CAT) play a central role. Our studies with mouse epidermal cells demonstrate that the balance between several antioxidant enzymes rather than the activity of a single component determines the degree of protection. Unexpectedly, increased levels of Cu,Zn-SOD alone in stable transfectants resulted in sensitization to oxidative chromosomal aberrations and DNA strand breaks. However, a concomitant increase in CAT or GPx in double transfectants corrected or overcorrected the hypersensitivity of the SOD clones depending on the ratios of activities CAT/SOD or GPx/SOD. The cellular antioxidant capacity also affected oxidant induction of the growth-related immediate early protooncogene c-fos. Increases in CAT or SOD reduced the accumulation of c-fos message, albeit for different reasons. The cellular antioxidant defense also affects the action of UVB light (290-320 nm) that represents the most potent carcinogenic wavelength range of the solar spectrum. UVB light is known to exert its action in part through oxidative mechanisms. Increases in CAT and GPx protected mouse epidermal cells from UVB-induced DNA breakage.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
The balance of antioxidant enzymes, including superoxide dismutases (SOD), glutathione peroxidases (GPx), and catalase (CAT), is crucial for cellular protection against oxidant damage and UVB radiation. Imbalances can lead to increased DNA damage.
Area of Science:
- Biochemistry
- Molecular Biology
- Carcinogenesis
Background:
- Oxidant carcinogens damage cellular components like DNA, leading to mutations and altered gene expression.
- Cells have antioxidant defense systems, notably superoxide dismutases (SOD), glutathione peroxidases (GPx), and catalase (CAT), to counteract oxidative stress.
- The interplay of genetic and epigenetic effects contributes to oxidant-induced carcinogenesis.
Purpose of the Study:
- To investigate the role of antioxidant enzyme balance in cellular protection against oxidant-induced damage.
- To determine how specific antioxidant enzymes influence sensitivity to DNA damage and gene expression.
- To assess the protective effects of antioxidant enzymes against UVB-induced DNA damage.
Main Methods:
- Generation of stable transfectants in mouse epidermal cells with altered levels of antioxidant enzymes (SOD, CAT, GPx).
- Assessment of sensitivity to oxidative chromosomal aberrations and DNA strand breaks.
- Analysis of oxidant and UVB-induced effects on gene expression (c-fos) and DNA integrity.
Main Results:
- Increased Cu,Zn-SOD alone sensitized cells to oxidative DNA damage.
- Concomitant increases in CAT or GPx corrected or overcorrected this hypersensitivity, depending on enzyme ratios.
- Enhanced CAT or SOD reduced oxidant-induced c-fos expression, while CAT and GPx protected against UVB-induced DNA breakage.
Conclusions:
- The balance between multiple antioxidant enzymes, not just individual activity, dictates cellular protection against oxidants.
- Antioxidant enzyme levels significantly modulate cellular responses to carcinogens and UV radiation.
- Targeting antioxidant enzyme balance may offer strategies for cancer prevention and treatment.