PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01.

Abstract

Most targeted anticancer drugs are inhibitors of kinases that are aberrantly activated in cancer cells. However, the mechanisms by which kinase inhibitors suppress tumor growth remain unclear. In this study, we found that UCN-01, a staurosporine analogue and broad-range kinase inhibitor used in clinical trials, inhibits colon cancer cell growth by inducing apoptosis via PUMA, a BH3-only Bcl-2 family member and a p53 target. PUMA expression was markedly elevated in a p53-independent fashion following UCN-01 treatment. The induction of PUMA by UCN-01 was mediated by direct binding of FoxO3a to the PUMA promoter following inhibition of AKT signaling. Deficiency in PUMA abrogated UCN-01-induced apoptosis, caspase activation, and mitochondrial dysfunction, and rendered UCN-01 resistance in a clonogenic assay, whereas elevated PUMA expression or a BH3 mimetic sensitized UCN-01 induced apoptosis. Chemosensitization by UCN-01 seemed to involve simultaneous PUMA induction through both p53-dependent and p53-independent mechanisms. Furthermore, deficiency in PUMA suppressed the antitumor effects of UCN-01 in a xenograft model, concurrent with reduced apoptosis and caspase activation in vivo. These results suggest that PUMA-mediated apoptosis is pivotal for the anticancer activities of UCN-01, and possibly other clinically used kinase inhibitor drugs, and that PUMA manipulation may be useful for improving their anticancer activities.

DOI: 10.1158/1535-7163.MCT-10-0635
050100150201220132014201520162017
Citations per Year

229 Citations

Semantic Scholar estimates that this publication has 229 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Dudgeon2010PUMAIB, title={PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01.}, author={Crissy S. Dudgeon and Peng Wang and Xiameng Sun and Rui Peng and Quanhong Sun and Jian Yu and Lin Zhang}, journal={Molecular cancer therapeutics}, year={2010}, volume={9 11}, pages={2893-902} }