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Activité PPARgamma-indépendante des ligands de PPAR gamma : une piste pour le traitement des cancers du sein ?

Abstract : One of the main goals of the anti-cancer research is to develop new therapeutic option for resistant tumor. In this context, the recent discovery of thiazolidinedione devoid of PPARγ activity with a strong anti-cancer effect opens new perspectives. In a previous study, the laboratory showed that an inactive derivative of PPARγ, the Δ2-TGZ, induce a proteasome-dependent degradation of estrogen receptor α in PPARγ-independent way. Thus, during my thesis we aimed 1) to participate in the study of new compounds less toxic and more effective to inhibit the proliferation of mammary cancer cells, 2) to better understand PPARγ-independent mechanisms involved in the anti-cancer effect of the TZD. In the present work, we characterise new compounds more effective than Δ2-TGZ to inhibit the proliferation of the breast cancer cells MCF-7 and MDA-MB-231 and are less toxic on primary culture of human hepatocytes. We pursued the study on mechanisms involved in PPARγ-independent antiproliferative activity of Δ2-TGZ. We showed that Δ2-TGZ is able to induce endoplasmic reticulum stress as soon as 3 hours and apoptosis in later times 48 hours of treatment. Nevertheless we could not conclude of the existence of a link between these two pathways. Finally, we studied the effect of the biotinylation of a natural ligand of PPARγ: the 15d-PGJ2. This modification drive to an increased effect of the 15d-PGJ2 on the anti-proliferative effect of breast cancer cells, reticulum endoplasmic stress and death by apoptosis. These effects are partially PPARγ-dependent for reticulum endoplasmic stress and only PPARγ-independent for apoptosis. This work highlighted new promising tools of breast cancers treatment.
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Contributor : Isabelle Grillier-Vuissoz Connect in order to contact the contributor
Submitted on : Thursday, December 12, 2013 - 4:31:22 PM
Last modification on : Saturday, October 16, 2021 - 11:14:12 AM


  • HAL Id : tel-00917937, version 1


Christelle Colin-Cassin. Activité PPARgamma-indépendante des ligands de PPAR gamma : une piste pour le traitement des cancers du sein ?. Sciences du Vivant [q-bio]. Université de Lorraine, 2013. Français. ⟨NNT : ⟩. ⟨tel-00917937⟩



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