Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Ophélie Meynet1,
  2. Barbara Zunino2,
  3. Lina Happo3,
  4. Ludivine A. Pradelli1,
  5. Johanna Chiche1,
  6. Marie A. Jacquin1,
  7. Laura Mondragón1,
  8. Jean-François Tanti4,
  9. Bruno Taillan5,
  10. Georges Garnier5,
  11. Julie Reverso-Meinietti6,
  12. Nicolas Mounier7,
  13. Jean-François Michiels6,
  14. Ewa M. Michalak8,
  15. Michel Carles9,
  16. Clare L. Scott10, and
  17. Jean-Ehrland Ricci1,*
  1. 1 Inserm, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), equipe "controle metabolique des morts cellulaires", Nice, France;
  2. 2 Universite de Nice-Sophia-Antipolis, Faculte de Medecine, Nice, France;
  3. 3 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;
  4. 4 Inserm, U1065, C3M, equipe "Cellular and Molecular Physiopathology of Obesity and Diabetes", France;
  5. 5 Centre Hospitalier Princess Grace de Monaco, Monaco;
  6. 6 Centre Hospitalier Universitaire de Nice, Departement d'anatomo-pathologie, Nice, France;
  7. 7 Centre Hospitalier Universitaire de Nice, Departement d'Onco-Hematologie, Nice, France;
  8. 8 The Netherlands Cancer Institute, Amsterdam, Netherlands;
  9. 9 Centre Hospitalier Universitaire de Nice, Departement d'Anesthesie Reanimation, Nice, France;
  10. 10 The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  1. * Corresponding author; email: ricci{at}unice.fr

Key points

  • 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.

Abstract

Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, understanding 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 CR by reducing protein translation, can reduce expression of the pro-survival Bcl-2-family member, Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. 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 either the BH3-only pro-apoptotic 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.

  • Submitted January 14, 2013.
  • Accepted July 7, 2013.