title: Cell fate after mitotic arrest in different tumor cells is determined by the balance between slippage and apoptotic threshold.
abstract: Microtubule poisons and other anti-mitotic drugs induce tumor death but the molecular events linking mitotic arrest to cell death are still not fully understood. We have analyzed cell fate after mitotic arrest produced by the microtubule-destabilizing drug vincristine in a panel of human tumor cell lines showing different response to vincristine. In Jurkat, RPMI 8226 and HeLa cells, apoptosis was triggered shortly after vincristine-induced mitotic arrest. However, A549 cells, which express a great amount of Bcl-x(L) and undetectable amounts of Bak, underwent mitotic slippage prior to cell death. However, when Bcl-x(L) gene was silenced in A549 cells, vincristine induced apoptosis during mitotic arrest. Another different behavior was found in MiaPaca2 cells, where vincristine caused death by mitotic catastrophe that switched to apoptosis when cyclin B1 degradation was prevented by proteasome inhibition. Overexpression of Bcl-x(L) or silencing Bax and Bak expression delayed the onset of apoptosis in Jurkat and RPMI 8226 cells, enabling mitotic slippage and endoreduplication. In HeLa cells, overexpression of Bcl-x(L) switched cell death from apoptosis to mitotic catastrophe. Mcl-1 offered limited protection to vincristine-induced cell death and Mcl-1 degradation was not essential for vincristine-induced death. All these results, taken together, indicate that the Bcl-x(L)/Bak ratio and the ability to degrade cyclin B1 determine cell fate after mitotic arrest in the different tumor cell types.
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Galán-Malo
authors.forename: Laura
authors.initials: L
authors.lastname: Vela
authors.forename: Oscar
authors.initials: O
authors.lastname: Gonzalo
authors.forename: Rubén
authors.initials: R
authors.lastname: Calvo-Sanjuán
authors.forename: Lucía
authors.initials: L
authors.lastname: Gracia-Fleta
authors.forename: Javier
authors.initials: J
authors.lastname: Naval
authors.forename: Isabel
authors.initials: I
authors.lastname: Marzo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050257:Tubulin Modulators / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D056744:Cyclin B1; D050257:Tubulin Modulators; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D014750:Vincristine