Anchorage of ∆2-Troglitazone on the dendrimer PAMAM demonstrates that early events in breast cancer cells occur independently of a nuclear action - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2013

Anchorage of ∆2-Troglitazone on the dendrimer PAMAM demonstrates that early events in breast cancer cells occur independently of a nuclear action

Résumé

Background: Resistance to therapies and the absence of targeted therapy for triple negative mammary tumors are strong arguments for the search for new therapeutic agents. Thiazolidinediones, synthetic PPARγ ligands, display antiproliferative effects in vitro and in vivo. Several studies suggest that it could be the result of PPARγ-independent mechanisms. We are working on the mechanism of action of ∆2-Troglitazone (∆2T), a derivative that does not activate the nuclear receptor PPARγ but still inhibits the proliferation of breast cancer cells. Our objective was to confirm the PPARγ-independent effect of ∆2T and to determine if ∆2T action was associated with other nuclear targets. Thus, we studied the effects of ∆2T anchored on the dendrimer PAMAM (polyamidoamine) that inhibits the entry into the nucleus. Methods: Rhodamine-∆2T (3 µM) and rhodamine-PAMAM-∆2T (43 nM) localisation in MCF7 cells was analysed by fluorescence microscopy. MCF7 cells were exposed to ∆2T (25 µM), PAMAM-∆2T (50 and 25 µM ∆2T equivalent meaning 4 and 2 µM of compound) and PAMAM (4 and 2 µM). Gene expression was analysed by RT-PCR. Proteins were analyzed by immunoblotting. Results: In contrast to Rhodamine-∆2T, rhodamine-PAMAM-∆2T is localized exclusively in the cytoplasm. PAMAM-∆2T induces the early effects of ∆2T: ERK1/2 phosphorylation, increase in EGR1 and NR4A1 (Nur77) mRNA level. However, we do not observe the cleavage of XBP1 mRNA, related to the endoplasmic reticulum (ER) stress. PAMAM-∆2T and ∆2T also induce the phosphorylation of the kinase AMPK (AMP dependent protein kinase) that could be involved in the response to energy restriction. Conclusion: This work allows us to demonstrate that most of the early events triggered by ∆2T are independent of an action on the nucleus. We have now to determine if later events such as the decrease of cell viability, the expression of ER stress (BIP, CHOP) and apoptotic (PARP and caspase 7) markers are also the result of a non-nuclear action of ∆2T.

Domaines

Cancer
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Dates et versions

hal-00919936 , version 1 (17-12-2013)

Identifiants

  • HAL Id : hal-00919936 , version 1

Citer

Audrey Berthe, Andrea Bordessa, Michel Boisbrun, Stéphane Flament, Sabine Mazerbourg. Anchorage of ∆2-Troglitazone on the dendrimer PAMAM demonstrates that early events in breast cancer cells occur independently of a nuclear action. 7ème forum Cancéropôle Grand-Est, Nov 2013, Strasbourg, France. page 40 résumé 31. ⟨hal-00919936⟩
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