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 EGFR-mediated signal transduction. RESULTS: Erlotinib significantly inhibited BrdU incorporation in BxPC-3 cells at a concentration of 1 μmol/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.
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 EGFR-mediated signal transduction. RESULTS:Erlotinib significantly inhibited BrdU incorporation in BxPC-3 cells at a concentration of 1 μmol/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.
Authors: J Spencer Liles; Juan Pablo Arnoletti; Ching-Wei D Tzeng; J Harrison Howard; Andrew V Kossenkov; Peter Kulesza; Martin J Heslin; Andrey Frolov Journal: Cancer Biol Ther Date: 2010-09-30 Impact factor: 4.742
Authors: H Friess; L Wang; Z Zhu; R Gerber; M Schröder; A Fukuda; A Zimmermann; M Korc; M W Büchler Journal: Ann Surg Date: 1999-12 Impact factor: 12.969
Authors: Caroline H Diep; Ruben M Munoz; Ashish Choudhary; Daniel D Von Hoff; Haiyong Han Journal: Clin Cancer Res Date: 2011-03-08 Impact factor: 12.531
Authors: Falko Lange; Benjamin Franz; Claudia Maletzki; Michael Linnebacher; Maja Hühns; Robert Jaster Journal: Biomed Res Int Date: 2014-09-17 Impact factor: 3.411
Authors: Christian Klopsch; Anna Skorska; Marion Ludwig; Heiko Lemcke; Gabriela Maass; Ralf Gaebel; Martin Beyer; Cornelia Lux; Anita Toelk; Karina Müller; Christian Maschmeier; Sarah Rohde; Petra Mela; Brigitte Müller-Hilke; Stefan Jockenhoevel; Brigitte Vollmar; Robert Jaster; Robert David; Gustav Steinhoff Journal: Dis Model Mech Date: 2018-06-22 Impact factor: 5.758