title: Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity-dependent suicidal inhibition of its polo-box domain.
abstract: Polo-like kinase 1 (Plk1) plays a critical role in proper M-phase progression and cell proliferation. Plk1 is overexpressed in a broad spectrum of human cancers and is considered an attractive anticancer drug target. Although a large number of inhibitors targeting the catalytic domain of Plk1 have been developed, these inhibitors commonly exhibit a substantial level of cross-reactivity with other structurally related kinases, thus narrowing their applicable dose for patient treatment. Plk1 contains a C-terminal polo-box domain (PBD) that is essentially required for interacting with its binding targets. However, largely due to the lack of both specific and membrane-permeable inhibitors, whether PBD serves as an alternative target for the development of anticancer therapeutics has not been rigorously examined. Here, we used an intracellularly expressed 29-mer-long PBIP1-derived peptide (i.e., PBIPtide), which can be converted into a "suicidal" PBD inhibitor via Plk1-dependent self-priming and binding. Using this highly specific and potent system, we showed that Plk1 PBD inhibition alone is sufficient for inducing mitotic arrest and apoptotic cell death in cancer cells but not in normal cells, and that cancer cell-selective killing can occur regardless of the presence or absence of oncogenic RAS mutation. Intriguingly, PBD inhibition also effectively prevented anchorage-independent growth of malignant cancer cells. Thus, targeting PBD represents an appealing strategy for anti-Plk1 inhibitor development. Additionally, PBD inhibition-induced cancer cell-selective killing may not simply stem from activated RAS alone but, rather, from multiple altered biochemical and physiological mechanisms, which may have collectively contributed to Plk1 addiction in cancer cells.
authors.affiliation: a Laboratory of Metabolism; National Cancer Institute; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: a Laboratory of Metabolism; National Cancer Institute; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Kim
authors.affiliation: b Incurable Diseases Therapeutics Research Center; Korea Research Institute of Bioscience and Biotechnology ; Ochang , Republic of Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: a Laboratory of Metabolism; National Cancer Institute; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D049452:Green Fluorescent Proteins; D006657:Histones; D009687:Nuclear Proteins; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000097869:Polo-Like Kinase 1; C485917:CENPU protein, human
keywords: Plk1; Polo-box domain; T78 peptide; anchorage-independent growth