title: Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells.
abstract: Polo-like kinase 1 (PLK1), a critical kinase that regulates multiple steps in mitosis, is overexpressed in diverse human cancers; thus many PLK1 inhibitors have been developed as potential cancer therapeutic agents. One of these compounds, the PLK1-specific inhibitor BI2536, has been investigated as a cytotoxic drug in several cancers, including lung cancer; however, the detailed mechanism by which BI2536 induces defects in cell proliferation of non-small cell lung cancer (NSCLC) has not yet been determined. We found that BI2536 treatment resulted in mitotic arrest due to improper formation of the mitotic spindles and mitotic centrosomes. The unattached kinetochores in BI2536-treated NSCLC cells activated the spindle assembly checkpoint (SAC). The prolonged activation of the SAC led to a type of apoptotic cell death referred to as mitotic catastrophe. Finally, BI2536-treated NSCLC cells show a defect in cell proliferation. Overall, these data indicate that PLK1 inhibition via mitotic disruption represents a potential approach for the treatment of NSCLC.
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Wootae
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Min Gyeong
authors.initials: MG
authors.lastname: Cheon
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi 440-746, Korea.
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea; Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 130-701, Korea. Electronic address: jekim@khu.ac.kr.
authors.forename: Ja Eun
authors.initials: JE
authors.lastname: Kim
mesh_terms: D050256:Antimitotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D059008:Time-Lapse Imaging; D000097869:Polo-Like Kinase 1
chemical_list: D050256:Antimitotic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536
keywords: BI2536; Mitosis; Mitotic catastrophe; Non-small cell lung cancer; PLK1; Spindle assembly checkpoint