Antonio Gómez-Muñoz
University of the Basque Country, Spain
Title: Regulation of pancreatic cancer cell migration by the axis ceramide kinase/ceramide 1 phosphate
Biography
Biography: Antonio Gómez-Muñoz
Abstract
Pancreatic cancer is an aggressive disease characterized by invasiveness, rapid progression and profound resistance to treatment. It is the fourth leading cause of cancer mortality with a 5-year survival rate of only 6%. Accumulating evidence indicates that sphingolipids play critical roles in cancer growth and dissemination. In particular, ceramide 1- phosphate (C1P), which is formed by the action of ceramide kinase on ceramide, stimulates cell proliferation (1), and promotes cell survival (2, 3). The mechanisms by which C1P stimulates cell growth involves activation of extracellularly regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), or mammalian target of rapamycin (mTOR), whereas C1P-enhanced cell survival implicates inhibition of serine palmitoyl transferase (SPT) and acid sphingomylinase (ASMase) (4). More recently, we found that 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. We also observed that human pancreatic cancer cells migrate spontaneously. However, contrary to the effect of C1P, spontaneous cell migration was insensitive to treatment with PTX (5). 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, 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, 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.