n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Carcinoma--Pancreatic-Ductal

The marked overexpression of cyclin-dependent kinase 5 (CDK5) or Notch1 receptor, which plays critical roles in pancreatic ductal adenocarcinoma (PDAC) development, has been detected in numerous PDAC cell lines and tissues. Although, a previous study has demonstrated that CDK5 inhibition disrupts Notch1 functions in human umbilical vein endothelial cells, the mechanism underlying Notch1 activation regulated by CDK5 remains unclear. Herein, we identified a physical interaction between CDK5 and Notch1 in PDAC cells, with the Notch1 peptide phosphorylated by CDK5/p25 kinase. CDK5 blockade resulted in the profound inhibition of Notch signaling. Accordingly, CDK5 inhibition sensitized PDAC cell proliferation and migration following Notch inhibition. In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration. The combinational inhibition of CDK5 and Notch signaling may be an effective strategy in the treatment of PDAC.

Topics: Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase 5; Dipeptides; Gene Silencing; Humans; Immunoprecipitation; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Receptor, Notch1; RNA, Messenger; Roscovitine; Signal Transduction

It was previously reported that γ-secretase inhibitors (GSIs) enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. To enable the development of taxane-based chemotherapy for pancreatic ductal adenocarcinoma (PDAC), this study investigated the molecular mechanisms by which γ-secretase (GS) complexes regulate taxane sensitivity.. The effect of GS complexes on taxane-induced apoptosis in PDAC cells was evaluated by a cell cycle analysis. GS complexes were examined with small interference RNAs targeted to GS complex-related genes.. GSIs and silencing of presenilin 1 (PS1) did not affect cell proliferation but resulted in enhanced taxane-induced G(2)/M accumulation and apoptosis. Silencing of the Notch gene did not induce these effects. However, PS2-specific silencing suppressed proliferation and taxane-induced apoptosis.. Data from this study indicate that GS complexes regulate the response of PDAC to taxanes through GS-dependent and GS-independent mechanisms.

Topics: Amyloid Precursor Protein Secretases; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Cycle; Dipeptides; Drug Synergism; Enzyme Inhibitors; Humans; Pancreatic Neoplasms; Presenilin-1; Presenilin-2; Receptors, Notch; Signal Transduction; Taxoids