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

Ophélie Meynet, Barbara Zunino, Lina Happo, Ludivine A. Pradelli, Johanna Chiche, Marie A. Jacquin, Laura Mondragón, Jean-François Tanti, Bruno Taillan, Georges Garnier, Julie Reverso-Meinietti, Nicolas Mounier, Jean-François Michiels, Ewa M. Michalak, Michel Carles, Clare L. Scott and Jean-Ehrland Ricci

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.