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Title

Delaying mitotic exit down-regulates FLIP expression and strongly sensitizes tumor cells to TRAIL

AuthorsSánchez-Pérez, Tania ; Medema, René H.; López-Rivas, Abelardo
Issue Date27-May-2013
PublisherCentro Nacional de Investigaciones Oncológicas Carlos III (España)
AbstractCell cycle deregulation is a feature of tumor cells. Most of the current therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Anti-mitotic drugs target different mitotic proteins impeding the assembly of a properly bipolar mitotic spindle which triggers mitotic checkpoint activation, mitotic arrest and eventually cell death. However, sometimes, after several hours of mitotic arrest, cells go out of mitosis by “slippage”. This failure to die during mitotic arrest seems to be the main mechanism of resistance to these treatments. Recently, in an attempt to avoid the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. In this study we show that treatments that induce mitotic checkpoint activation and mitotic arrest downregulate FLIP levels and sensitize several tumor cell lines to TRAIL-induced apoptosis. We also demonstrate that in the absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or over-expression of nondegradable Cyclin B is sufficient to induce both FLIP down-regulation and sensitivity to TRAIL. Interestingly, our data suggest that a combination of anti-mitotic drugs targeting Cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, facilitating tumor suppression
DescriptionPóster presentado en el CNIO Frontiers Meetings: Chromosome Instability and Aneuploidy in Cancer: From Mechanisms to Therapeutics, celebrado en Madrid del 27 al 29 de mayo de 2013
URIhttp://hdl.handle.net/10261/123978
Appears in Collections:(CABIMER) Comunicaciones congresos
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