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Updated: May 3, 2026
Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis
Published on: February 16, 2015
Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis
Yves Matthess1, Monika Raab2, Rainald Knecht3
1Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
Abstract:
Caspase-8 is crucial for cell death induction, especially via the death receptor pathway. The dysregulated expression or function of caspase-8 can promote tumor formation, progression and treatment resistance in different human cancers. Here, we show procaspase-8 is regulated during the cell cycle through the concerted inhibitory action of Cdk1/cyclin B1 and polo-like kinase 1 (Plk1). By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis. Thus, the clinical Plk1 inhibitor BI 2536 decreases the threshold of different cancer cell types toward Fas-induced cell death.
Insights
Cell cycle regulation of caspase-8 by Cdk1/cyclin B1 and Plk1 phosphorylation inhibits extrinsic cell death during mitosis. This finding suggests Plk1 inhibitors may enhance cancer cell death sensitivity.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Caspase-8 is vital for initiating programmed cell death via the death receptor pathway.
- Aberrant caspase-8 activity is implicated in cancer development, progression, and resistance to therapy.
Purpose of the Study:
- To investigate the cell cycle regulation of procaspase-8.
- To elucidate the roles of Cdk1/cyclin B1 and Plk1 in modulating caspase-8 activity.
- To determine the impact of caspase-8 phosphorylation on extrinsic cell death sensitivity.
Main Methods:
- RNA interference (RNAi) to deplete endogenous caspase-8.
- Site-directed mutagenesis to create non-phosphorylatable caspase-8 mutants (S305A).
- Fas-stimulation assays to assess extrinsic cell death induction.
Main Results:
- Procaspase-8 is sequentially phosphorylated by Cdk1/cyclin B1 (at S387) and Plk1 (at S305) during mitosis.
- Mitotic phosphorylation by Cdk1/cyclin B1 and Plk1 reduces cellular sensitivity to extrinsic death receptor pathway stimuli.
- A non-phosphorylatable caspase-8 mutant (S305A) enhances Fas-induced cell death.
Conclusions:
- Sequential phosphorylation of procaspase-8 by Cdk1/cyclin B1 and Plk1 acts as a cell cycle-dependent brake on extrinsic apoptosis during mitosis.
- Targeting Plk1 with inhibitors like BI 2536 may sensitize various cancer types to Fas-mediated cell death, offering a potential therapeutic strategy.
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