Cholecystokinin-2 receptor modulates cell adhesion through beta 1-integrin in human pancreatic cancer cells.
Several lines of evidence suggest that gastrin and the CCK-2 receptor (CCK2R) could contribute to pancreatic carcinogenesis by modulating processes such as proliferation, cell adhesion or migration. In the current study, we used a 'cancer gene array' and identified beta1-integrin subunit as a new gastrin-regulated gene in human pancreatic cancer cells. We also demonstrated that Src family kinases and the phosphatidylinositol-3-kinase (PI-3-kinase) pathway play a crucial role in the expression of beta1-integrin induced by gastrin. Our results also showed that gastrin modulates cell-substrate adhesion via beta1-integrin. Indeed, using blocking anti-beta1-integrin monoclonal antibodies, we completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we observed that in response to gastrin, beta1-integrin is tyrosine phosphorylated by Src family kinases and associates with paxillin, a scaffold protein involved in focal adhesion and integrin signalling. This mechanism might be involved in gastrin-induced cell adhesion. Moreover, we showed in vivo that targeted CCK2R expression in the pancreas of Elas-CCK2 mice leads to the overexpression of beta1-integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.
INSERM U 531, IFR 31, Institut Louis Bugnard, Toulouse, France.
C
C
Cayrol
P
P
Clerc
C
C
Bertrand
V
V
Gigoux
G
G
Portolan
D
D
Fourmy
M
M
Dufresne
C
C
Seva
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D005755:Gastrins / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000502:physiology*
D005755:Gastrins; D019012:Integrin beta1; D043887:Receptor, Cholecystokinin B