Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics

// Camila Rubio-Patino 1, 2 , Jozef P. Bossowski 1, 2 , Elodie Villa 1, 2 , Laura Mondragon 1, 2 , Barbara Zunino 1, 2 , Emma Proics 1, 2, 3 , Johanna Chiche 1, 2 , Frederic Bost 2, 4 , Els Verhoeyen 1, 2 , Jean-Ehrland Ricci 1, 2 1 Inserm, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Equipe “Controle Metabolique des Morts Cellulaires”, Nice, France 2 Universite Nice Cote d’Azur, Inserm, C3M, France 3 Centre Hospitalier Universitaire de Nice, Departement d’Anesthesie Reanimation, Nice, France 4 Inserm, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Equipe “Cellular and Molecular Physiopathology of Obesity and Diabetes”, Nice, France Correspondence to: Jean-Ehrland Ricci, email: ricci@unice.fr Keywords: metabolism, cancer, resistance to treatment, Mcl-1, low carbohydrate diet Received: May 27, 2016      Accepted: September 19, 2016      Published: September 28, 2016 ABSTRACT Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food. Indeed, feeding lymphoma-bearing mice with a diet having 25% less carbohydrates was sufficient to decrease Mcl-1 expression by 50% in lymphoma cells. We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 (eEF2) inhibition, blocking protein translation elongation. Strikingly, a low CHO diet was sufficient to sensitize Myc-driven lymphoma-bearing mice to ABT-737-induced cell death in vivo . Thus reducing carbohydrate intake may represent a safe way to decrease Mcl-1 expression and to sensitize tumor cells to anti-cancer therapeutics.