Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase andenhancing GLUT-1 expression

Pancreatic carcinoma is characterized by poor prognosis and lack of respons e to conventional therapy for reasons that are not clear. Because of the st ructural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regu lated by pancreatic islet hormones, particularly insulin. Based on this, th e effect of islet hormones on pancreatic cancer cells in vitro was investig ated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaP aCa2 were used to investigate the effect of islet hormones on cell prolifer ation, glucose utilization, and GLUT-1 expression. Insulin, but not somatos tatin and glucagon, induced pancreatic cancer cell growth in a concentratio n- and time-dependent manner. At concentrations within the range of those i n the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [H-3]-thymidine incorporation. Insulin significantly:enhanced glu cose utilization of pancreatic cancer cells before it enhanced cell prolife ration. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DN A synthesis and partially reduced insulin-stimulated glucose uptake. In con trast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin- induced glucose uptake and partially blocked thymidine incorporation. Furth ermore, after 24-hour treatment with insulin, GLUT-1 expression in pancreat ic cancer cells was markedly increased, indicating that insulin enhances gl ucose utilization partly through increasing glucose transport. These findin gs suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA syn thesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kin ase activation and enhancement of GLUT-1 expression. High intrapancreatic c oncentrations of insulin are likely to play an important role in stimulatin g pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.