Titre :

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors

Auteur(s) :

Muller, Claire []
Centre de Recherche en Automatique de Nancy [CRAN]
Lacroix-Malgras, Victorine []
Centre de Recherche en Automatique de Nancy [CRAN]
Kluza, Jérôme [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Laine, William [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Güler, Yonca [Auteur]
Centre de Recherche en Automatique de Nancy [CRAN]
Bost, Frédéric [Auteur]
Centre méditerranéen de médecine moléculaire [C3M]
Boisbrun, Michel [Auteur]
Laboratoire Lorrain de Chimie Moléculaire [L2CM]
Mazerbourg, Sabine [Auteur correspondant]
Centre de Recherche en Automatique de Nancy [CRAN]
Flament, Stéphane [Auteur]
Centre de Recherche en Automatique de Nancy [CRAN]

Titre de la revue :

Cancer Cell International

Pagination :

132

Éditeur :

BioMed Central

Date de publication :

2024-04-10

ISSN :

1475-2867

Mot(s)-clé(s) en anglais :

Glycolysis
Oxygen consumption
Complex I
Breast cancer
Thiazolidinediones
Troglitazone
Energy metabolism
Mitochondria

Discipline(s) HAL :

Sciences du Vivant [q-bio]
Chimie

Résumé en anglais : [en]

Background: The metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties can potentially ...
Lire la suite >Background: The metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties can potentially be exploited for therapeutic intervention. In this context, we have developed troglitazone derivatives to treat hormone-sensitive and triple-negative breast cancers, which currently lack therapeutic targets, have an aggressive phenotype, and often have a worse prognosis than other subtypes. Here, we studied the metabolic impact of the EP13 compound, a desulfured derivative of Δ2-troglitazone that we synthetized and is more potent than its parent compounds.Methods: EP13 was tested on two triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T, and on the luminal cell line MCF-7. The oxygen consumption rate (OCR) of the treated cell lines, Hs578T mammospheres and isolated mitochondria was measured using the XFe24 Seahorse analyser. ROS production was quantified using the MitoSOX fluorescent probe. Glycolytic activity was evaluated through measurement of the extracellular acidification rate (ECAR), glucose consumption and lactate production in extracellular medium. The synergistic effect of EP13 with glycolysis inhibitors (oxamate and 2-deoxyglucose) on cell cytotoxicity was established using the Chou-Talalay method.Results: After exposure to EP13, we observed a decrease in the mitochondrial oxygen consumption rate in MCF7, MDA-MB-231 and Hs578T cells. EP13 also modified the maximal OCR of Hs578T spheroids. EP13 reduced the OCR through inhibition of respiratory chain complex I. After 24 h, ATP levels in EP13-treated cells were not altered compared with those in untreated cells, suggesting compensation by glycolysis activity, as shown by the increase in ECAR, the glucose consumption and lactate production. Finally, we performed co-treatments with EP13 and glycolysis inhibitors (oxamate and 2-DG) and observed that EP13 potentiated their cytotoxic effects.Conclusion: This study demonstrates that EP13 inhibits OXPHOS in breast cancer cells and potentiates the effect of glycolysis inhibitors.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277

Source :

Harvested from HAL