Implication of ceramide kinase and ceramide 1-phosphate in pancreatic cancer

Résumé

Pancreatic cancer is an aggressive and devastating disease that is characterized by invasiveness, rapid progression and profound resistance to treatment. Despite recent advances in surgical and medical therapy, little progress has been made to decrease the mortality rate of patients with pancreatic cancer. It is now well established that sphingolipids are important signaling molecules in diverse cellular processes. Some sphingolipids including ceramides and ceramide 1-phosphate (C1P) have been involved in the control of cell homeostasis. For many years, our group has focused on the role of C1P in the regulation of cell growth and survival and more recently we discovered that C1P promotes chemotaxis. In this thesis, we demonstrate that C1P enhances cell migration and invasion of human pancreatic cancer cells. These actions of C1P implicate the activation of two major pathways: Phosphatidylinositol 3-kinase (PI3K)/Akt and MEK/ERK1-2. We also demonstrate the involvement of Ceramide Kinase (CERK), the enzyme responsible for synthesis of C1P in mammalian cells, in tumorigenesis and metastasis in pancreatic cancer cells. Specifically, we found that CERK is involved in the Epithelial to Mesenchymal Transition (EMT) process. We also demonstrate that CERK and C1P regulate the secretion of VEGF, IL-8, MCP-1 and TGF-ß1, which are all important tumorigenic factors. Moreover, we present evidence suggesting that C1P promotes angiogenic processes, which can eventually lead to the formation of new blood vessels. These findings place C1P as a novel promoter of tumorigenesis, and open up a new avenue that may allow the design of alternative therapeutic strategies for treatment of cancer.