title: Bcl-xL controls a switch between cell death modes during mitotic arrest.
abstract: Antimitotic agents such as microtubule inhibitors (paclitaxel) are widely used in cancer therapy while new agents blocking mitosis onset are currently in development. All these agents impose a prolonged mitotic arrest in cancer cells that relies on sustained activation of the spindle assembly checkpoint and may lead to subsequent cell death by incompletely understood molecular events. We have investigated the role played by anti-apoptotic Bcl-2 family members in the fate of mitotically arrested mammary tumor cells treated with paclitaxel, or depleted in Cdc20, the activator of the anaphase promoting complex. Under these conditions, a weak and delayed mitotic cell death occurs that is caspase- and Bax/Bak-independent. Moreover, BH3 profiling assays indicate that viable cells during mitotic arrest are primed to die by apoptosis and that Bcl-xL is required to maintain mitochondrial integrity. Consistently, Bcl-xL depletion, or treatment with its inhibitor ABT-737 (but not with the specific Bcl-2 inhibitor ABT-199), during mitotic arrest converts cell response to antimitotics to efficient caspase and Bax-dependent apoptosis. Apoptotic priming under conditions of mitotic arrest relies, at least in part, on the phosphorylation on serine 62 of Bcl-xL, which modulates its interaction with Bax and its sensitivity to ABT-737. The phospho-mimetic S62D-Bcl-xL mutant is indeed less efficient than the corresponding phospho-deficient S62A-Bcl-xL mutant in sequestrating Bax and in protecting cancer cells from mitotic cell death or yeast cells from Bax-induced growth inhibition. Our results provide a rationale for combining Bcl-xL targeting to antimitotic agents to improve clinical efficacy of antimitotic strategy in cancer therapy.
authors.affiliation: Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France.
authors.forename: N
authors.initials: N
authors.lastname: Bah
authors.affiliation: Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France.
authors.forename: L
authors.initials: L
authors.lastname: Maillet
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France.
authors.forename: S
authors.initials: S
authors.lastname: Dubreil
authors.affiliation: 1] Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France [2] Institut de Cancérologie de l'Ouest (ICO), Centre de Lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, Saint Herblain-Nantes 44805, France [3] Plateforme IMPACT Biogenouest, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France.
authors.forename: F
authors.initials: F
authors.lastname: Gautier
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: A
authors.initials: A
authors.lastname: Letai
authors.affiliation: 1] Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France [2] Institut de Cancérologie de l'Ouest (ICO), Centre de Lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, Saint Herblain-Nantes 44805, France.
authors.forename: P
authors.initials: P
authors.lastname: Juin
authors.affiliation: Team 8 'Cell survival and Tumor Escape in Breast Cancer', UMR 892 INSERM/6299 CNRS/Université de Nantes, Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, Nantes 1 44007, France.
authors.forename: S
authors.initials: S
authors.lastname: Barillé-Nion
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C501332:ABT-737; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein