Insights into erlotinib action in pancreatic cancer cells using a combined experimental and mathematical approach
Insights into erlotinib action in pancreatic cancer cells using a combined experimental and mathematical approach作者机构：Department of Systems Biology and Bioinformatics University of Rostock 18057 Rostock Germany Department of Medicine Ⅱ Division of Gastroenterology University Medicine Rostock 18057 Rostock Germany Stellenbosch Institute for Advanced Study Wallenberg Research Centre at Stellenbosch University Stellenbosch 7600 South Africa
出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)
年 卷 期：2012年第18卷第43期
页 面：6226-6234页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：Supported by A grant of the Bundesministerium für Bildung und Forschung through the FORSYS partner program, No.0315255 the Helmholtz Society as part of the Systems Biology Network
主 题：Erlotinib Pancreatic cancer Epidermal growth factor receptor Signal transduction Mathematical modeling
摘 要：AIM:To gain insights into the molecular action of erlotinib in pancreatic cancer (PC) cells. METHODS:Two PC cell lines, BxPC-3 and Capan-1, were treated with various concentrations of erlotinib, the specific mitogen-activated protein kinase kinase (MEK) inhibitor U0126, and protein kinase B (AKT) inhibitor XIV. DNA synthesis was measured by 5-bromo-2 -deoxyuridine (BrdU) assays. Expression and phosphorylation of the epidermal growth factor receptor (EGFR) and downstream signaling molecules were quantified by Western blot analysis. The data were processed to calibrate a mathematical model, based on ordinary differential equations, describing the EGFRmediated signal transduction. RESULTS:Erlotinib significantly inhibited BrdU incorporation in BxPC-3 cells at a concentration of 1 mol/L, whereas Capan-1 cells were much more resistant. In both cell lines, MEK inhibitor U0126 and erlotinib attenuated DNA synthesis in a cumulative manner, whereas the AKT pathway-specific inhibitor did not enhance the effects of erlotinib. While basal phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) did not differ much between the two cell lines, BxPC-3 cells displayed a more than five-times higher basal phospho-AKT level than Capan-1 cells. Epidermal growth factor (EGF) at 10 ng/mL induced the phosphorylation of EGFR, AKT and ERK in both cell lines with similar kinetics. In BxPC-3 cells, higher levels of phospho-AKT and phospho-ERK (normalized to the total protein levels) were observed. Independent of the cell line, erlotinib efficiently inhibited phosphorylation of EGFR, AKT and ERK. The mathematical model successfully simulated the experimental findings and provided predictions regarding phosphoprotein levels that could be verified experimentally. CONCLUSION:Our data suggest basal AKT phosphorylation and the degree of EGF-induced activation of AKT and ERK as molecular determinants of erlotinib efficiency in PC cells.
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