Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice

• Published in: Blood 2013-10, Vol.122 (14), p.2402-2411
• Main Authors: Meynet, Ophélie, Zunino, Barbara, Happo, Lina, Pradelli, Ludivine A., Chiche, Johanna, Jacquin, Marie A., Mondragón, Laura, Tanti, Jean-François, Taillan, Bruno, Garnier, Georges, Reverso-Meinietti, Julie, Mounier, Nicolas, Michiels, Jean-François, Michalak, Ewa M., Carles, Michel, Scott, Clare L., Ricci, Jean-Ehrland
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein - metabolism; Biphenyl Compounds - pharmacology; Caloric Restriction; Disease Models, Animal; Drug Resistance, Neoplasm - physiology; Lymphoma, B-Cell - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols - pharmacology; Piperazines - pharmacology; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Sulfonamides - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-01-478651

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. •Caloric restriction reduces Mcl-1 expression and sensitizes lymphoma cells to ABT-737 in vivo.•Caloric restriction mimetics can sensitize lymphomas to ABT-737–induced death independently of p53 and of the main BH3-only proteins.