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Redox regulation of protein kinase C by selenometabolites and selenoprotein thioredoxin reductase limits cancer prevention by selenium
- Source :
- Free Radical Biology and Medicine. 127:55-61
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- The cancer-preventive mechanism of selenium should address the way low concentrations of selenometabolites react with cellular targets without being diffused from the sites of generation, the way selenium selectively kills tumor cells, and the intriguing U-shaped curve that is seen with dietary supplementation of selenium and cancer prevention. Protein kinase C (PKC), a receptor for tumor promoters, is well suited for this mechanism. Due to the catalytic redox cycle, low concentrations of methylselenol, a postulated active metabolite of selenium, react with the tumor-promoting lipid hydroperoxide bound to PKC to form methylseleninic acid (MSA), which selectively reacts with thiol residues present within the vicinity of the PKC catalytic domain to inactivate it. Given that lipid hydroperoxide levels are high in promoting cells, PKC inactivation selectively leads to death in these cells. A biphasic effect of MSA in inducing cell death was observed in certain prostate cancer cell lines; lower concentrations of MSA induced cell death, while higher concentrations failed to do so. Lower concentrations of selenium inactivate more sensitive antiapoptotic isoenzymes of PKC (ε and α), sparing less sensitive proapoptotic isoenzymes (PKCδ and PKCζ). Higher concentrations of selenium also inactivate proapoptotic isoenzymes and consequently make tumor cells resistant to apoptosis. Due to a high-affinity binding of thioredoxin to the PKC catalytic domain, this thiol oxidation is explicitly reversed by thioredoxin reductase (TXNRD), a selenoprotein. Therefore, overexpression of TXNRD in advanced tumor cells could make them resistant to selenium-induced death. Conceivably, this mechanism, at least in part, explains why selenium prevents cancer only in certain cases.
- Subjects :
- 0301 basic medicine
Programmed cell death
Thioredoxin-Disulfide Reductase
Thioredoxin reductase
chemistry.chemical_element
Biochemistry
Selenium
03 medical and health sciences
0302 clinical medicine
Neoplasms
Physiology (medical)
Animals
Humans
Selenoproteins
Receptor
Protein Kinase C
Protein kinase C
chemistry.chemical_classification
Chemistry
Isoenzymes
Cell Transformation, Neoplastic
030104 developmental biology
Apoptosis
030220 oncology & carcinogenesis
Selenoprotein
Thioredoxin
Oxidation-Reduction
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine
- Accession number :
- edsair.doi.dedup.....a154c477e6444853aa1970c3d6186173