Abstract
Plk1 is a checkpoint protein whose role spans all of mitosis and includes DNA repair, and is highly conserved in eukaryotes from yeast to man. Consistent with this wide array of functions for Plk1, the cellular consequences of Plk1 disruption are diverse, spanning delays in mitotic entry, mitotic spindle abnormalities, and transient mitotic arrest leading to mitotic slippage and failures in cytokinesis. In this work, we present the in vitro and in vivo consequences of Plk1 inhibition in cancer cells using potent, selective small-molecule Plk1 inhibitors and Plk1 genetic knock-down approaches. We demonstrate for the first time that cellular senescence is the predominant outcome of Plk1 inhibition in some cancer cell lines, whereas in other cancer cell lines the dominant outcome appears to be apoptosis, as has been reported in the literature. We also demonstrate strong induction of DNA double-strand breaks in all six lines examined (as assayed by γH2AX), which occurs either during mitotic arrest or mitotic-exit, and may be linked to the downstream induction of senescence. Taken together, our findings expand the view of Plk1 inhibition, demonstrating the occurrence of a non-apoptotic outcome in some settings. Our findings are also consistent with the possibility that mitotic arrest observed as a result of Plk1 inhibition is at least partially due to the presence of unrepaired double-strand breaks in mitosis. These novel findings may lead to alternative strategies for the development of novel therapeutic agents targeting Plk1, in the selection of biomarkers, patient populations, combination partners and dosing regimens.
Highlights
The disruption of mitotic progression is a commonly used and clinically effective strategy for treating cancer
Plk1 inhibition leads to mitotic delays and DNA damage MLN0905 is a potent experimental small molecule inhibitor of
MLN0905 was used to study the induction of mitotic delays and DNA damage following Plk1 inhibition in cells
Summary
The disruption of mitotic progression is a commonly used and clinically effective strategy for treating cancer. High-content live-cell imaging techniques have revealed a striking diversity of responses to the same agent across a range of cell lines [5] [6] [7], and importantly, heterogeneous, stochastic responses within the same cell line [5]. These more comprehensive characterizations, with real-time techniques, have in general yielded a more diverse picture of the duration and downstream consequences of mitotic arrest
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