Cancer Cell Biology
Inhibition of CDK4 impairs proliferation of pancreatic cancer cells and sensitizes towards TRAIL-induced apoptosis via downregulation of survivin
Version of Record online: 15 FEB 2007
Copyright © 2007 Wiley-Liss, Inc.
International Journal of Cancer
Volume 121, Issue 1, pages 66–75, 1 July 2007
How to Cite
Retzer-Lidl, M., Schmid, R. M. and Schneider, G. (2007), Inhibition of CDK4 impairs proliferation of pancreatic cancer cells and sensitizes towards TRAIL-induced apoptosis via downregulation of survivin. Int. J. Cancer, 121: 66–75. doi: 10.1002/ijc.22619
- Issue online: 24 APR 2007
- Version of Record online: 15 FEB 2007
- Manuscript Accepted: 12 JAN 2007
- Manuscript Received: 8 SEP 2006
- Deutsche Forschungsgemeinschaft. Grant Number: SFB456
- pancreatic cancer;
Pancreatic ductal adenocarcinoma is one of the most common causes of cancer death in Western countries with an average survival after diagnosis of 3–6 months and a five-year survival rate under 5%. Because of the lack of effective therapies, there is the need to characterize new molecular treatment strategies. Abnormal regulation of the cell cycle is a hallmark of neoplasia. Cyclin-dependent kinase 4 (CDK4), a key regulator of G1-phase of the cell cycle, has been shown to be overexpressed in pancreatic cancer. Until now, the contribution of CDK4 to tumor maintenance of pancreatic cancer has not been investigated. In this study, we used the chemical CDK4 inhibitor 2-bromo-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, as well as RNA interference, to investigate the function of CDK4 in pancreatic cancer cells. Both approaches led to a reduction of pancreatic cancer cell proliferation due to G1-phase cell cycle arrest and Rb activation. Furthermore, we observed increased sensitivity of G1-arrested pancreatic cancer cells towards TRAIL-induced apoptosis. Sensitization towards TRAIL was due to the transcriptional downregulation of survivin. These findings show that a combined sensitizer/inducer strategy may be a potential therapeutic strategy for pancreatic ductal adenocarcinoma. © 2007 Wiley-Liss, Inc.