Effects of cerulein on keratin 8 phosphorylation and perinuclear reorganization in pancreatic cancer cells: Involvement of downregulation of protein phosphatase 2A and alpha4.

Toxicants can perturb cellular homeostasis by modifying phosphorylation-based signaling. In the present study, we examined the effects of cerulein, an inducer of acute pancreatitis, on keratin 8 (K8) phosphorylation. We found that cerulein dose-dependently induced K8 phosphorylation and perinuclear reorganization in PANC-1 cells, thus leading to migration and invasion. The extracellular signal-regulated kinases (ERK) inhibitor U0126 suppressed cerulein-induced phosphorylation of serine 431 and reorganization of K8. Cerulein reduced the expressions of protein phosphatase 2A (PP2A) via ubiqutination and alpha4. PP2A's involvement in K8 phosphorylation of PANC-1 cells was also confirmed by the observation that PP2A gene silencing resulted in K8 phosphorylation and migration of PANC-1 cells. Overall, these results suggest that cerulein induced phosphorylation and reorganization through ERK activation by downregulating PP2A and alpha4, leading to increased migration and invasion of PANC-1 cells.