Growth effects of regulatory peptides and intracellular signaling routes in human pancreatic cancer cell lines.
The intracellular events involved in normal pancreatic growth have been extensively investigated in response to cholecystokinin. Recent data indicate that tyrosine kinase, phospholipase D, phosphatidylinositol 3-kinase, and p42/p44 MAPK are stimulated in rat pancreatic acinar cells. Although we begin to understand the intracellular signaling pathways activated in normal pancreas, such information is not yet available in pancreatic cancer cells. This study was undertaken to identify the growth factors and hormones involved in cell proliferation of two human pancreatic cancer cell lines of ductal origin, the MIA PaCa-2, and PANC-1 cells, and to establish the intracellular events involved in the control of their growth. We demonstrated that FGF-2, IGF-1, cerulein, and gastrin but not FGF-1, HGF, secretin, and PACAP, stimulated proliferation of MIA PaCa-2 and PANC-1 cells. Autocrine factors such as gastrin and IGF-1 were also responsible for their proliferation. In response to EGF, FGF-2, IGF-1, cerulein, gastrin and bombesin, tyrosine kinase, and tyrosine phosphatase activities were stimulated in both cell lines. The close relationship established between cell growth and tyrosine kinase activation results from the observation that maximal growth stimulation paralleled with maximal enzyme activation and that genistein, the tyrosine kinase inhibitor, blocked cell growth and enzyme activation. The implication of PLD in growth-stimulated processes is doubtful since all growth factors and hormones tested failed to stimulate an already very active PLD activity. We finally observed a constitutive activity of p44 MAPK in both cell lines and of p42 in MIA PaCa-2 cells. However, p38 and p42 were stimulated in MIA PaCa-2 and PANC-1 cells, respectively, by all growth factors and hormones.
Douziech
N
N
Department de Médecine, Faculté de Médecine, Université de Sherbrooke, Québec, Canada.
Lajas
A
A
Coulombe
Z
Z
Calvo
E
E
Lainé
J
J
Morisset
J
J
D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002108:Ceruletide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005755:Gastrins / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010739:Phospholipase D / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D005755:Gastrins; D006133:Growth Substances; D006728:Hormones; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D002108:Ceruletide; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D010739:Phospholipase D; D001839:Bombesin