The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.
Fiche publication
Date publication
janvier 2024
Journal
Cancer letters
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian, Dr GROSS Isabelle, Dr MASSON Murielle, Dr MELLITZER Georg, Dr VENKATASAMY Aina
Tous les auteurs :
Riegel G, Orvain C, Recberlik S, Spaety ME, Poschet G, Venkatasamy A, Yamamoto M, Nomura S, Tsukamoto T, Masson M, Gross I, Le Lagadec R, Mellitzer G, Gaiddon C
Lien Pubmed
Résumé
Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.
Mots clés
Caspase-independent apoptosis, ER stress, Glutathione, Metabolism, RDC11, Transsulfuration, UPR
Référence
Cancer Lett. 2024 01 28;:216671