23^rd International Conference on
Cancer Research & Pharmacology

Biography:

Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao (Spain)

Abstract:

Pancreatic cancer is the fourth leading cause of cancer mortality with a 5-year survival rate of only 6%. This aggressive disease is characterized by invasiveness, rapid progression and profound resistance to treatment. Using an in vitro cell migration assay we have found that ceramide 1-phosphate (C1P) enhances human pancreatic cancer cell migration and invasion potently and that this effect is completely abolished by pertussis toxin (PTX), suggesting the participation of a Gi protein-coupled receptor in this process. Activation of the C1P receptor caused phosphorylation and activation of ERK1-2 and Akt, and inhibition of these kinases abolished C1P-stimulated cell migration/invasion. We have also observed that human pancreatic cancer PANC-1 and Mia PaCa-2 cells migrate spontaneously. Contrary to the effect of C1P, spontaneous cell migration was insensitive to treatment with PTX. Investigation into the mechanisms responsible for spontaneous migration of the pancreatic cancer cells revealed that ceramide kinase (CerK) is a key enzyme in the regulation of this process. In fact, inhibition of CerK activity with the selective inhibitor NVP-231, or treatment with specific CerK siRNA to silence the gene encoding this kinase, potently reduced migration of the pancreatic cancer cells. By contrast, overexpression of CerK stimulated cell migration, an action that was concomitant with prolonged phosphorylation of ERK1-2 and Akt, which are kinases involved in C1P-stimulated cell migration/invasion, in a PTX independent manner. It can be concluded that the axis CerK/C1P plays a critical role in pancreatic cancer cell migration/invasion, and that targeting CerK expression or activity may be a relevant factor for controlling pancreatic cancer cell dissemination.