The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein
| Autor: | M. Bhonde, Kimitoshi Kohno, Peter T. Daniel, Dhatchana Moorthy, M.L. Hanski, Antje Müller, C. Hanski, Roberta Magrini, Martin Zeitz, Edward A. Sausville, Peter Wiegand |
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| Rok vydání: | 2004 |
| Předmět: |
STAT3 Transcription Factor
endocrine system Cancer Research Cell cycle checkpoint bcl-X Protein Antineoplastic Agents Apoptosis Protein Serine-Threonine Kinases Biology Cyclin-dependent kinase Proto-Oncogene Proteins Tumor Cells Cultured otorhinolaryngologic diseases Genetics Humans STAT3 Molecular Biology Inhibitor of apoptosis domain Kinase Carcinoma NF-kappa B Cell cycle Staurosporine Cyclin-Dependent Kinases DNA-Binding Proteins Gene Expression Regulation Neoplastic Proto-Oncogene Proteins c-bcl-2 Colonic Neoplasms Trans-Activators Cancer research biology.protein Proto-Oncogene Proteins c-akt G1 phase |
| Zdroj: | Oncogene. 24:148-156 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1207842 |
| Popis: | 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-x(L) on mRNA and protein level. In contrast, in the apoptosis-resistant cell lines, Bcl-x(L) expression was not affected by UCN-01. Stable overexpression of the Bcl-x(L) 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-x(L) expression in colon carcinoma cells. Moreover, we show for the first time that UCN-01 induces apoptosis by suppression of Bcl-x(L) expression. The inhibition of this pathway is a new aspect of cytotoxic and modulatory potential of UCN-01. |
| Databáze: | OpenAIRE |
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