Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival.
Cancer cell adhesion and invasion into extracellular matrix are regulated by integrin-linked kinase (ILK) activity in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. In this study, we demonstrated that ILK and beta(1)-integrin play important roles in interleukin (IL)-1alpha-induced enhancement of adhesion and invasion of pancreatic cancer cells through p38 mitogen-activated protein kinase (MAPK) signaling pathway and activator protein-1 (AP-1) activation. Alteration of ILK kinase activity controlled IL-1alpha-induced p38 MAPK phosphorylation and its downstream AP-1 activation with subsequent regulation of pancreatic cancer cell adhesion and invasion. Overexpressed ILK enhances the IL-1alpha-induced p38 MAPK phosphorylation more strongly through glycogen synthase kinase 3 (GSK-3) activation, and subsequently induces AP-1 activation, which promotes aggressive capabilities of pancreatic cancer cells. In contrast, knockdown of ILK kinase activity inhibits the IL-1alpha-induced activation of MAPK/AP-1 pathway via inhibition of GSK-3 phosphorylation. In immunohistochemical analysis, statistically significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients were observed, and strong expression of ILK in cancerous tissues can be a significant prognostic indicator of pancreatic cancer patients. Our results suggest that ILK is involved with aggressive capability in pancreatic cancer and that these regulations can be helpful to understand biological processes for a better translational treatment for pancreatic cancer patients.
Sawai
H
H
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. cb8h-swi@asahi-net.or.jp
Okada
Y
Y
Funahashi
H
H
Matsuo
Y
Y
Takahashi
H
H
Takeyama
H
H
Manabe
T
T
D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism* / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016019:Survival Analysis; D000099200:Scaffold Protein ILK
D019012:Integrin beta1; D007375:Interleukin-1; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK