Thioredoxin reductase and selenium in carcinogenesis and multidrug resistance

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Sammanfattning: The thioredoxin system, comprising thioredoxin, thioredoxin reductase (TrxR) and NADPH, is a redox system of great importance in the defence against oxidative stress and is involved in the regulation of several cellular processes, such as apoptosis and cell proliferation. In addition, TrxR is a selenoenzyme and is a key enzyme in selenium metabolism. The aim of this study was to elucidate the role of TrxR in carcinogenesis and in resistant cancer cells and to investigate the tumor preventive effects and the cytotoxicity of selenium compounds. In this study we have defined the subcellular localisation and recorded activity alterations of TrxR in a rat model for chemically induced hepatocarcinogenesis. Enzymatic activity as well as mRNA expression of TrxR was found to be four times higher in premalignant neoplastic liver lesions than in normal liver. The cytosolic TrxR activity increased in the premalignant liver tissue during the carcinogenetic process compared to control tissue whereas the mitochondrial activity decreased. During the promotion phase selenite administration significantly decreased the volume fraction of preneoplastic liver nodules in parallel with a decrease in cell proliferation in the lesions. Selenite administration during the progression phase resulted in a lower volume fraction of liver tumors and a decreased proliferation within the tumors. If the selenite treatment was limited to the phase of diethylnitrosamine initiation only, no effect was seen on the number or volume fraction of preneoplastic liver lesions. In an attempt to find new therapeutic strategies to cancers resistant to common chemotherapy we have examined the cytotoxic effect of selenite in multidrug resistant cancer cells. Drugresistant cells appeared to be considerably more sensitive to selenite cytotoxicity than drugsensitive cells. Further studies showed presence of caspase-independent selenite-induced apoptosis in the drug-resistant cells. The selenite sensitivity observed in the drug-resistant cells was not associated with the up-regulation of TrxR seen in the drug-sensitive cells during selenite exposure. To further investigate the role of TrxR in selenite cytotoxicity, we used cells over-expressing this enzyme. The TrxR over-expressing cells showed an increased resistance towards selenite cytotoxicity compared to control cells. After preincubation with selenite, in a low, enzymesaturating dose, an even higher resistance against selenite toxicity was obtained. In conclusion, our data suggest that TrxR is important in neoplastic liver lesions and demonstrate that selenium supplementation prevent the carcinogenetic process both during the promotion and progression phases. Moreover, we report selenite-induced apoptosis occurring in the drug-resistant cells and an increase in TrxR activity appears to be crucial for cell resistance against selenium cytotoxicity.

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