Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a disease of nearly complete lethality presenting a median survival time of 6 months, and is predicted to become the second leading cause of cancer-related deaths before 2030.1 This may be explained by the vast majority of patients presenting with advanced stages of pancreatic ductal adenocarcinoma (PDAC) at diagnosis, and PDAC cells possess a high metastatic potential and are often resistant to available cytotoxic drugs.[2]
We investigated the crosstalk between cyclin-dependent kinase 5 (CDK5) and Notch[1] signaling in PDAC cells
As active CDK5/ p25 kinase is located in Golgi membranes,[8,9] the two proteins might colocalize in the Golgi network
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a disease of nearly complete lethality presenting a median survival time of 6 months, and is predicted to become the second leading cause of cancer-related deaths before 2030.1 This may be explained by the vast majority of patients presenting with advanced stages of PDAC at diagnosis, and PDAC cells possess a high metastatic potential and are often resistant to available cytotoxic drugs.[2]. The cleavage of p35 and p39 to p25 and p29, respectively, yields activators with greater stability and increased CDK5 kinase activation when compared with that of observed with the full-length forms of p35 and p39.7 CDK5 is mainly activated by p35 or its truncated product, p25, and the active CDK5/p25 kinase is present in Golgi membranes in neurons.[8,9] the role of CDK5 in the central system is well characterized, it has been recently associated with the development and progression of multiple cancers, including brain, breast, lung, colon, and pancreatic cancer.[7,10] Accumulating evidence has implicated CDK5 as an important determinant of malignant progression, invasion, and metastasis in PDAC.[11,12] CDK5 is widely active, and p35 and p39 are significantly overexpressed in PDAC.[13] both CDK5 and Notch[1] are important proteins that affect PDAC cell growth, invasion, and metastasis. We investigated the crosstalk between CDK5 and Notch[1] signaling in PDAC cells
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