title: Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL.
abstract: Proapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors: J
authors: J
authors: Le Pen
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors: L
authors: L
authors: Maillet
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: K
authors: K
authors: Sarosiek
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors: C
authors: C
authors: Vuillier
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Institut de Cancérologie de l'Ouest, Centre de Lutte contre le Cancer René Gauducheau, Saint Herblain, France.
authors: F
authors: F
authors: Gautier
authors: Department of Cell Biology, University of Geneva, Geneva,Switzerland.
authors: S
authors: S
authors: Montessuit
authors: Department of Cell Biology, University of Geneva, Geneva,Switzerland.
authors: J C
authors: JC
authors: Martinou
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: A
authors: A
authors: Letaï
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors: F
authors: F
authors: Braun
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 'Cell Survival And Tumor Escape In Breast Cancer', Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Institut de Cancérologie de l'Ouest, Centre de Lutte contre le Cancer René Gauducheau, Saint Herblain, France.
authors: P P
authors: PP
authors: Juin
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D040761:Biomimetic Materials / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C501332:ABT-737; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein