Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics.
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.
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Camila
C
Rubio-Patiño
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Jozef P
JP
Bossowski
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Elodie
E
Villa
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Laura
L
Mondragón
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Barbara
B
Zunino
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.|Centre Hospitalier Universitaire de Nice, Département d'Anesthésie Réanimation, Nice, France.
Emma
E
Proïcs
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Johanna
J
Chiche
Université Nice Côte d'Azur, Inserm, C3M, France.|Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Cellular and Molecular Physiopathology of Obesity and Diabetes", Nice, France.
Frédéric
F
Bost
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Els
E
Verhoeyen
Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe "Contrôle Métabolique des Morts Cellulaires", Nice, France.|Université Nice Côte d'Azur, Inserm, C3M, France.
Jean-Ehrland
JE
Ricci
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000067558:Biological Mimicry; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050528:Diet, Carbohydrate-Restricted; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
Mcl-1; cancer; low carbohydrate diet; metabolism; resistance to treatment
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