title: Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism.
abstract: Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Waraky
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
authors.forename: Karen
authors.initials: K
authors.lastname: Akopyan
authors.affiliation: Axelar AB, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: Vendela
authors.initials: V
authors.lastname: Parrow
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Strömberg
authors.affiliation: Department of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.affiliation: Axelar AB, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Abrahmsén
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Lindqvist
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden. Alexandria University, Faculty of Science, Department of Zoology, Alexandria, Egypt. The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children's Hospital, University of Arizona College of Medicine-Phoenix, Department of Child Health, Phoenix, Arizona, USA.
authors.forename: Eiman
authors.initials: E
authors.lastname: Aleem
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D002470:Cell Survival / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D034622:RNA Interference; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D014404:Tubulin; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D011034:Podophyllotoxin