The mitotic spindle checkpoint is a critical determinant for topoisomerase-based chemotherapy
Celia Vogel1, Anne Kienitz, Rolf Müller
1Institute for Molecular Biology and Tumor Research (IMT), Philipps University Marburg, D-35037 Marburg, Germany.
Abstract:
A novel strategy in cancer therapy is the induction of mitotic cell death by the pharmacological abrogation of cell cycle checkpoints. UCN-01 is such a compound that overrides the G2 cell cycle arrest induced by DNA damage and forces cells into a deleterious mitosis. The molecular pathways leading to mitotic cell death are largely unknown although recent evidence indicates that mitotic cell death represents a special case of apoptosis. Here, we demonstrate that the mitotic spindle checkpoint is activated upon chemotherapeutic treatment with topoisomerase II poisons and UCN-01. Cells that are forced to enter mitosis in the presence of topoisomerase inhibition arrest transiently in a prometaphase like state. By using a novel pharmacological inhibitor of the spindle checkpoint and spindle checkpoint-deficient cells we show that the spindle checkpoint function is required for the mitotic arrest and, most importantly, for efficient induction of mitotic cell death. Thus, our results demonstrate that the mitotic spindle checkpoint is an important determinant for the outcome of a chemotherapy based on the induction of mitotic cell death. Its frequent inactivation in human cancer might contribute to the observed resistance of tumor cells to these chemotherapeutic drugs.
Insights
The mitotic spindle checkpoint is crucial for chemotherapy effectiveness, ensuring cancer cells undergo programmed cell death. Its inactivation may lead to drug resistance in tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cancer therapy increasingly targets cell cycle regulation to induce mitotic cell death.
- UCN-01 overrides G2 arrest, forcing cells into mitosis, but the underlying mechanisms of mitotic cell death are unclear.
- Mitotic cell death is increasingly recognized as a distinct form of apoptosis.
Purpose of the Study:
- To investigate the role of the mitotic spindle checkpoint in chemotherapy-induced mitotic cell death.
- To elucidate the molecular pathways involved when cells are forced into mitosis under genotoxic stress.
Main Methods:
- Utilizing topoisomerase II inhibitors and UCN-01 to induce mitotic stress.
- Employing a novel spindle checkpoint inhibitor and spindle checkpoint-deficient cells for functional analysis.
- Observing cell cycle progression and cell death following chemotherapeutic treatment.
Main Results:
- The mitotic spindle checkpoint is activated by topoisomerase II poisons and UCN-01.
- Cells treated with topoisomerase inhibitors and forced into mitosis exhibit a transient prometaphase arrest.
- Spindle checkpoint function is essential for both mitotic arrest and efficient induction of mitotic cell death.
Conclusions:
- The mitotic spindle checkpoint is a critical determinant for chemotherapy efficacy when targeting mitotic cell death.
- Inactivation of the spindle checkpoint in human cancers may confer resistance to certain chemotherapeutic agents.
- Targeting the spindle checkpoint could be a strategy to overcome chemotherapy resistance.
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