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6. Transdifferentiation of Human Islet Cells in a Long-term Culture

Author

Schmied, Bruno M., primary, Ulrich, Alexis, additional, Matsuzaki, Hosei, additional, Ding, Xianzhong, additional, Ricordi, Camillo, additional, Weide, Lamont, additional, Moyer, Mary Pat, additional, Batra, Surinder K., additional, Adrian, Thomas E., additional, and Pour, Parviz M., additional

Published
2001
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18. Physiological Concentrations of Insulin Augment Pancreatic Cancer Cell Proliferation and Glucose Utilization By Activating MAP Kinase, PI3Kinase and Enhancing GLUT-1 Expression

Author

Ding, Xian-Zhong, Fehsenfeld, Drew M., Murphy, Leon O., Permert, Johan, and Adrian, Thomas E.

Abstract

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 (10−10–10−8mol/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 PI3kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-1 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 PI3kinase activation and enhancement of GLUT-1 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.

Published
2000

19. On the mechanisms of 12-O-tetradecanoylphorbol-13-acetate-induced growth arrest in pancreatic cancer cells.

Author

Salabat MR, Ding XZ, Flesche JB, Ujiki MB, Robin TP, Talamonti MS, Bell RH Jr, and Adrian TE

Subjects
Cell Division, Cell Line, Tumor, Cyclin A metabolism, Cyclin B metabolism, Cyclin B1, Cyclin E metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Flavonoids pharmacology, G2 Phase, Humans, Indoles pharmacology, MAP Kinase Kinase Kinases antagonists & inhibitors, MAP Kinase Kinase Kinases metabolism, Maleimides pharmacology, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Phosphorylation, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Protein Kinase Inhibitors pharmacology, RNA, Messenger metabolism, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Pancreatic Neoplasms pathology, Tetradecanoylphorbol Acetate pharmacology
Abstract

Objectives: Protein kinase C (PKC) is involved in cell growth, differentiation, and apoptosis. We investigated the effects of the PKC activator, the tetradecanylphorbol acetate (TPA), in human pancreatic cancer cells., Methods: Cell proliferation was measured by thymidine incorporation. Expression of cell cycle proteins was investigated by Western blot. Real-time reverse transcriptase-polymerase chain reaction was used to measure p21 messenger RNA expression, whereas knockdown of its expression was accomplished with a specific small interferring RNA. Cell cycle phases were determined by flow cytometry., Results: TPA time and concentration dependently inhibited thymidine incorporation in Panc-1 and CD18 cells and induced G2/M cell cycle arrest. The TPA decreased cyclin A and B expression, increased cyclin E, and markedly increased the expression of p21 at both the messenger RNA and protein levels. TPA-induced p21 expression and growth inhibition were blocked by the PKC inhibitor, bisindoylmaleimide. TPA induced extracellular signal-regulated kinase1/2 phosphorylation, whereas the MEK inhibitor, PD98059, blocked the TPA-induced p21 expression. Small interferring RNA targeted to p21 blocked TPA-induced p21 protein expression but not TPA-induced cell growth arrest., Conclusions: TPA-induced p21 expression is mediated by the MEK/ERK pathway but is not involved in TPA-induced growth inhibition. In contrast, cyclin A and cyclin B are likely involved in TPA-induced G2/M arrest because both proteins are involved in S phase and G2/M transition during cell proliferation.

Published
2006
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