title: Plk1 inhibition causes post-mitotic DNA damage and senescence in a range of human tumor cell lines.
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.
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Driscoll
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Arijit
authors.initials: A
authors.lastname: Chakravarty
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Doug
authors.initials: D
authors.lastname: Bowman
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Kerri
authors.initials: K
authors.lastname: Lasky
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Shi
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Tricia
authors.initials: T
authors.lastname: Vos
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Amidon
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: D'Amore
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Hyer
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1