Abstract
The mitotic spindle checkpoint represents a signal transduction pathway that prevents the onset of anaphase until all chromosomes are properly aligned on a metaphase plate. Partial inactivation of this checkpoint allows premature separation of sister chromatids and results in aneuploidy, which might contribute to tumorigenesis. Unlike other cell cycle checkpoints, the spindle checkpoint is essential for cell viability, giving rise to the idea that the spindle checkpoint itself might represent a valuable target for anticancer therapy. We used a cell-based screen and identified the indolocarbazole compound Gö6976 as a pharmacologic inhibitor of the spindle checkpoint. Gö6976 potently overrides a spindle checkpoint-mediated mitotic arrest by abrogating the phosphorylation and kinetochore localization of several spindle checkpoint proteins. We identified the Aurora-A and Aurora-B kinases, which have been previously implicated in proper mitotic progression and spindle checkpoint function, as targets for Gö6976. Accordingly, Gö6976 treatment causes severe mitotic abnormalities and chromosome alignment defects, which are not properly detected by the drug-inactivated spindle checkpoint. This results in an aberrant progression of mitosis, leading to apoptosis in various human cancer cell lines, including spindle checkpoint-compromised cancer cells. Thus, our work describes a novel and promising strategy for anticancer treatment that targets the mitotic spindle checkpoint.
Highlights
Antimitotic drugs, including various taxanes and Vinca alkaloids, are frequently used for anticancer treatment [1]
Activation of the spindle checkpoint in response to misaligned chromosomes either in the early phases of a regular mitosis or chronically on antimitotic drug treatment causes the inhibition of the ubiquitin ligase activity within the anaphase-promoting complex/cyclosome (APC/C), which is required for the degradation of various mitotic substrates, including securin and cyclin B
Because several kinases are involved in spindle checkpoint signaling, we screened commercially available protein kinase 1inhibitors, including established inhibitors for protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase (CDK), Chk1, mitogenactivated protein/extracellular signal-regulated kinase kinase, p38, Raf, and phosphatidylinositol 3-kinase (Fig. 1B)
Summary
Antimitotic drugs, including various taxanes and Vinca alkaloids, are frequently used for anticancer treatment [1]. The druginduced and spindle checkpoint–mediated mitotic arrest is followed by the induction of apoptosis, which occurs either in mitosis or in the postmitotic G1 phase on escape from a prolonged mitotic arrest [4]. The latter decision might depend on two. Activation of the spindle checkpoint in response to misaligned chromosomes either in the early phases of a regular mitosis or chronically on antimitotic drug treatment causes the inhibition of the ubiquitin ligase activity within the anaphase-promoting complex/cyclosome (APC/C), which is required for the degradation of various mitotic substrates, including securin and cyclin B. Failure of the spindle checkpoint results in a premature separation of sister chromatids and an unscheduled exit from mitosis, which leads to the generation of aneuploid progenitors [2, 3]
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