PUMA Induction by FoxO3a Mediates the Anticancer Activities of the Broad-Range Kinase Inhibitor UCN-01
- 1 November 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 9 (11), 2893-2902
- https://doi.org/10.1158/1535-7163.mct-10-0635
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. Mol Cancer Ther; 9(11); 2893–902. ©2010 AACR.Other Versions
This publication has 52 references indexed in Scilit:
- PUMA is directly activated by NF-κB and contributes to TNF-α-induced apoptosisCell Death & Differentiation, 2009
- PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cellsOncogene, 2009
- PUMA, a potent killer with or without p53Oncogene, 2008
- PUMA Regulates Intestinal Progenitor Cell Radiosensitivity and Gastrointestinal SyndromeCell Stem Cell, 2008
- Sp1 and p73 activate PUMA following serum starvationCarcinogenesis: Integrative Cancer Research, 2008
- The BH3-only protein Puma plays an essential role in cytokine deprivation–induced apoptosis of mast cellsBlood, 2007
- p53 independent induction of PUMA mediates intestinal apoptosis in response to ischaemia-reperfusionGut, 2007
- The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damageProceedings of the National Academy of Sciences of the United States of America, 2007
- FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawalThe Journal of Experimental Medicine, 2006
- The Hallmarks of CancerCell, 2000