Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL.
Many of the current antitumor therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Antimitotic drugs trigger mitotic checkpoint activation, mitotic arrest and eventually cell death. However, mitotic slippage represents a major mechanism of resistance to these treatments. In an attempt to circumvent 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 FLICE-like inhibitory protein (FLIP) levels and sensitize several tumor cell lines to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. Interestingly, we also demonstrate that in absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or overexpression of nondegradable cyclin B is sufficient to induce both FLIP downregulation and sensitivity to TRAIL. In summary, our data suggest that a combination of antimitotic drugs targeting cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, thereby facilitating tumor suppression.
1] Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Sevilla, Spain [2] Division of cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Sánchez-Pérez
Division of cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Medema
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Sevilla, Spain.
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López-Rivas
D050256:Antimitotic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis* / Q000235:genetics; D064199:Cdc20 Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics
D050256:Antimitotic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D064199:Cdc20 Proteins; D019926:Cyclin B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C577488:CDC20 protein, human