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The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

Oncogene volume 24, pages 148–156 (2005)Cite this article

Abstract

The broad-range cyclin-dependent kinase inhibitor 7-hydroxystaurosporine (UCN-01) is known to induce both a G1 cell cycle arrest and apoptosis. The mechanism of UCN-01-induced apoptosis is largely unknown. We analysed the mechanism of cytotoxicity of UCN-01 in four established colon carcinoma cell lines. The cell lines SW48 and LS513 responded to UCN-01 treatment by undergoing apoptosis in a concentration-dependent manner while the cell lines HT-29 and WiDr were completely resistant. Apoptosis in LS513 and SW48 cell lines was concomitant with the suppression of Bcl-xL on mRNA and protein level. In contrast, in the apoptosis-resistant cell lines, Bcl-xL expression was not affected by UCN-01. Stable overexpression of the Bcl-xL protein abrogated UCN-01-triggered apoptosis, but only partially restored growth, indicating that both cell cycle arrest and apoptosis exert the anticancer effect in a coordinated manner. The inhibition of Akt phosphorylation did not correlate with the apoptotic phenotype. UCN-01 inhibited the activating STAT3 phosphorylations on Ser727 and, notably, on Tyr705, but STAT3 did not contribute to Bcl-xL expression in colon carcinoma cells. Moreover, we show for the first time that UCN-01 induces apoptosis by suppression of Bcl-xL expression. The inhibition of this pathway is a new aspect of cytotoxic and modulatory potential of UCN-01.

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Abbreviations

p53wt:

p53 wild type

p53mut:

p53 mutated

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Acknowledgements

The excellent technical assistance of Britta Jebautzke is acknowledged. Mandar Bhonde and Roberta Magrini were supported by the Sonnenfeld-Stiftung.

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Authors and Affiliations

  1. Department of Gastroenterology, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Mandar R Bhonde, Marie-Luise Hanski, Roberta Magrini, Dhatchana Moorthy, Martin Zeitz & Christoph Hanski

  2. Department of Clinical and Molecular Oncology, Campus Berlin-Buch, Berlin, Germany

    Antje Müller & Peter T Daniel

  3. National Cancer Institute, Rockville, USA

    Edward A Sausville

  4. University of Occupational and Environmental Health, School of Medicine, Kitakyoushu, Japan

    Kimitoshi Kohno

  5. Institute of Forensic Medicine, Ulm, Germany

    Peter Wiegand

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  1. Mandar R Bhonde
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Correspondence to Christoph Hanski.

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Bhonde, M., Hanski, ML., Magrini, R. et al. The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein. Oncogene 24, 148–156 (2005). https://doi.org/10.1038/sj.onc.1207842

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