Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

Journal article


Waraky, A., Akopyan, K., Parrow, V., Strömberg, T., Axelson, M., Abrahmsén, L., Lindqvist, A., Larsson, O. and Aleem, E. (2014). Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism. Oncotarget. 5 (18), pp. 8379-8392. https://doi.org/10.18632/oncotarget.2292
AuthorsWaraky, A., Akopyan, K., Parrow, V., Strömberg, T., Axelson, M., Abrahmsén, L., Lindqvist, A., Larsson, O. and Aleem, E.
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.

KeywordsCentrosome; Microtubules; Animals; Humans; Lung Neoplasms; Podophyllotoxin; Tubulin; Cyclin-Dependent Kinases; CDC2 Protein Kinase; Receptors, Somatomedin; Antineoplastic Agents; Xenograft Model Antitumor Assays; Transfection; Signal Transduction; Mitosis; Apoptosis; Cell Survival; RNA Interference; Enzyme Activation; Time Factors; Cyclin B1; Hep G2 Cells; G2 Phase Cell Cycle Checkpoints; MCF-7 Cells
Year2014
JournalOncotarget
Journal citation5 (18), pp. 8379-8392
PublisherImpact Journals, LLC
ISSN1949-2553
Digital Object Identifier (DOI)https://doi.org/10.18632/oncotarget.2292
Publication dates
Print01 Jan 2014
Online31 Jul 2014
Publication process dates
Accepted31 Jul 2014
Deposited02 Feb 2021
Publisher's version
License
File Access Level
Open
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