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Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

Oncogene volume 21, pages 3162–3171 (2002)Cite this article

Abstract

A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suffering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identified which suppress PLK1 mRNA and protein in a dose-dependent and sequence-specific manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20–30%) of cells in G2/M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative effects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.

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Acknowledgements

We are grateful to B Hüls and O Möbert for their excellent technical support. This work was supported by grants from the Deutsche Krebshilfe (10-1212-St 1), the DFG (STR/8-1), the Messer Stiftung and the Dresdner Bank.

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  1. Birgit Spänkuch-Schmitt and Georg Wolf: B Spänkuch-Schmitt and G Wolf contributed equally to this work

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, JW Goethe University, Theodor-Stern-Kai 7, Frankfurt, 60596, Germany

    Birgit Spänkuch-Schmitt, Georg Wolf, Christine Solbach, Sibylle Loibl, Manfred Stegmüller, Gunter von Minckwitz, Manfred Kaufmann & Klaus Strebhardt

  2. Department of Otorhinolaryngology, School of Medicine, JW Goethe University, Theodor-Stern-Kai 7, Frankfurt, 60596, Germany

    Rainald Knecht

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  1. Birgit Spänkuch-Schmitt
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Correspondence to Klaus Strebhardt.

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Spänkuch-Schmitt, B., Wolf, G., Solbach, C. et al. Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 21, 3162–3171 (2002). https://doi.org/10.1038/sj.onc.1205412

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