Inhibition of CDK4 impairs proliferation of pancreatic cancer cells and sensitizes towards TRAIL-induced apoptosis via downregulation of survivin.
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.
Retzer-Lidl
Michaela
M
II Department of Internal Medicine, Technical University of Munich, Munich, Germany.
Schmid
Roland M
RM
Schneider
Günter
G
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4