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Implication du système thiorédoxine dans la régulation des phosphatases CDC25 dans des cellules de cancer du sein en condition de stress oxydant

Abstract : Recent studies suggest that the regulation of phosphatases by hydrogen peroxide may play an important role in cell signaling. In cancer cells, which often possess a pro-oxidative redox state, this regulation could be essential for tumor growth. CDC25 phosphatases (A, B and C) are key regulators of cell cycle progression. Sohn and Rudolph have shown that CDC25B and C are inactivated by hydrogen peroxide and reactivated by the thioredoxin/thioredoxin reductase system (trx/trxR), in vitro. Such regulation in cancer cells could open new therapeutic avenues since the inhibition of trxR or trx could induce a CDC25 inhibition and so prevent tumor cell multiplication. After verifying that CDC25 activity is sensitive to H202 and could be restored by trx/trxR system in vitro, the effects of hydrogen peroxide and that of two trx/trxR inhibitors (Auranofin and Acrolein) was tested on human breast adenocarcinoma cells (MCF7 and MDA-MB 231). These two cell lines exhibit differential expression level for trx1. In both cell lines, H202 could induce a cell cycle arrest in spite of the lack of a full CDC25 inhibition. The maintenance of the CDK phosphorylation state suggests that an efficient protective system exists for these phosphatases. The total inhibition of trxR by Auranofin led to cytotoxic effects and peroxide production in both cell lines. Similar results were obtained for MDA-MB 231 cells treated with Acrolein while MCF7 cells were found to be resistant to this compound. Auranofin could trigger a moderate oxidative stress in treated cells without affecting intracellular GSH content, trx1 oxidation and cell cycle distribution. However, this treatment could trigger double-strand DNA breaks, which could explain the cytotoxicity of Auranofin. Conversely, Acrolein could provoke a strong GSH depletion associated with a full oxidation of trx1 and a cell cycle arrest in MDA-MB 231 cells. Nevertheless, this cell cycle disruption was not due to CDK hyper-phosphorylation, suggesting that a total inhibition of the trx/trxR system does not trigger a full CDC25 inhibition. Furthermore, in order to bring additional knowledge about CDC25 and cell cycle oxidative regulation in breast cancer cells, we have studied the effects of the Mn-SOD over-expression in MCF7 cells. In this cell line, Mn-SOD expression level was found to be lower than in MDA-MB 231 cells. Our results showed that the cell cycle distribution and CDK phosphorylation are not affected by Mn-SOD over-expression. In conclusion, we have shown in this work that the CDC25 function in cell cycle regulation is independent of both a functional trx/trxR system and Mn-SOD expression level but that, under pro-oxidative conditions, a potent protective system maintains at least partially CDC25 dephosphorylation activity in breast cancer cells
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Submitted on : Thursday, March 29, 2018 - 12:00:13 PM
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Adeline Beillerot. Implication du système thiorédoxine dans la régulation des phosphatases CDC25 dans des cellules de cancer du sein en condition de stress oxydant. Médecine humaine et pathologie. Université Paul Verlaine - Metz, 2011. Français. ⟨NNT : 2011METZ027S⟩. ⟨tel-01749067⟩



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