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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

Item Type:Article
Title:The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein
Creators Name:Bhonde, M.R. and Hanski, M.L. and Magrini, R. and Moorthy, D. and Mueller, A. and Sausville, E.A. and Kohno, K. and Wiegand, P. and Daniel, P.T. and Zeitz, M. and Hanski, C.
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-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.
Keywords:Colon carcinoma, Chemotherapy, UCN-01, Apoptosis, Cell cycle arrest
Source:Oncogene
ISSN:0950-9232
Publisher:Nature Publishing Group (U.K.)
Volume:24
Page Range:148-156
Date:6 January 2005
Official Publication:https://doi.org/10.1038/sj.onc.1207842
PubMed:View item in PubMed

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