title: Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice.
abstract: Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.
authors: Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires," Institut national de la santé et de la recherche médicale (Inserm) U1065, Nice, France;
authors: Ophélie
authors: O
authors: Meynet
authors: Barbara
authors: B
authors: Zunino
authors: Lina
authors: L
authors: Happo
authors: Ludivine A
authors: LA
authors: Pradelli
authors: Johanna
authors: J
authors: Chiche
authors: Marie A
authors: MA
authors: Jacquin
authors: Laura
authors: L
authors: Mondragón
authors: Jean-François
authors: JF
authors: Tanti
authors: Bruno
authors: B
authors: Taillan
authors: Georges
authors: G
authors: Garnier
authors: Julie
authors: J
authors: Reverso-Meinietti
authors: Nicolas
authors: N
authors: Mounier
authors: Jean-François
authors: JF
authors: Michiels
authors: Ewa M
authors: EM
authors: Michalak
authors: Michel
authors: M
authors: Carles
authors: Clare L
authors: CL
authors: Scott
authors: Jean-Ehrland
authors: JE
authors: Ricci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D031204:Caloric Restriction; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides