title: YM155 potently triggers cell death in breast cancer cells through an autophagy-NF-kB network.
abstract: Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. We herein show that YM155 exerts single agent toxicity on primary breast cancer cells grown in an ex vivo assay preserving tumor microenvironment. In vitro assays indicate that YM155 more efficiently triggers cell death in breast cancer cells (including these with stem-cell like properties) than in non tumorigenic mammary cells. YM155-induced cell death is critically dependent on autophagy and NF-kB but independent of p53 and it coïncides with DNA damage and a DNA damage response in p53-proficient cells. Our results point out a crosstalk between NF-kB and autophagy controlling YM155-induced death in breast cancer cells and argue for the potential use of YM155 as a genotoxic agent in breast cancer therapy.
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors.forename: Eloïse
authors.initials: E
authors.lastname: Véquaud
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Séveno
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Service d'Anatomie Pathologique, HGRL, CHU, Nantes University, Nantes, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Loussouarn
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Engelhart
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Institut de Cancérologie de Nantes, Centre de lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Institut de Cancérologie de Nantes, Centre de lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.affiliation: CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Barillé-Nion
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D016328:NF-kappa B; D009285:Naphthoquinones; C523798:sepantronium
keywords: breast cancer; ex vivo assay; therapy