Ding X Z, Fehsenfeld D M, Murphy L O, Permert J, Adrian T E
Department of Biomedical Sciences, Creighton University, School of Medicine, Omaha, Nebraska 68178, USA.
Pancreas. 2000 Oct;21(3):310-20. doi: 10.1097/00006676-200010000-00014.
Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural 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 regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.
胰腺癌的特点是预后较差，且对传统疗法反应不佳，原因尚不清楚。由于外分泌胰腺和内分泌胰腺之间的结构关系，以及高浓度胰岛激素作用于胰腺组织，我们推测胰腺癌细胞的增殖和葡萄糖利用受胰岛激素调控，尤其是胰岛素。基于此，我们研究了胰岛激素对体外胰腺癌细胞的影响。使用五种胰腺癌细胞系CD11、CD18、HPAF、PANC - 1和MiaPaCa2来研究胰岛激素对细胞增殖、葡萄糖利用和葡萄糖转运蛋白1（GLUT - 1）表达的影响。胰岛素而非生长抑素和胰高血糖素以浓度和时间依赖性方式诱导胰腺癌细胞生长。在胰腺内血管系统中的浓度范围内，胰岛素（10⁻¹⁰ - 10⁻⁸ mol/L）显著增加[³H] -胸腺嘧啶核苷掺入。胰岛素在增强细胞增殖之前显著增强了胰腺癌细胞的葡萄糖利用。丝裂原活化蛋白激酶（MAPK）激酶抑制剂PD 098059消除了胰岛素刺激的DNA合成，并部分降低了胰岛素刺激的葡萄糖摄取。相反，磷脂酰肌醇3激酶（PI3激酶）抑制剂渥曼青霉素显著抑制胰岛素诱导的葡萄糖摄取，并部分阻断胸腺嘧啶核苷掺入。此外，用胰岛素处理24小时后，胰腺癌细胞中的GLUT - 1表达显著增加，表明胰岛素部分通过增加葡萄糖转运来增强葡萄糖利用。这些发现表明胰岛素通过两条不同途径刺激胰腺癌细胞的增殖和葡萄糖利用。胰岛素主要通过激活MAP激酶增加DNA合成，主要通过激活PI3激酶和增强GLUT - 1表达增加葡萄糖摄取。胰腺内高浓度的胰岛素可能通过增加底物可用性间接刺激胰腺癌生长，以及作为一种营养因子直接发挥作用，从而起到重要作用。
