This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsuda, K. Articles by Korc, M. Search for Related Content PubMed PubMed Citation Articles by Matsuda, K. Articles by Korc, M.

Multiple Mitogenic Pathways in Pancreatic Cancer Cells Are Blocked by a Truncated Epidermal Growth Factor Receptor¹

Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine, Biological Chemistry, and Pharmacology [K. M., T. I., M. K.], and Department of Molecular Biology and Biochemistry [X. J. Y., N. H. K., H. F.], University of California, Irvine, California 92697

The epidermal growth factor (EGF) receptor (EGFR) family consists of four transmembrane tyrosine kinases that undergo homodimerization and heterodimerization. Pancreatic cancers overexpress these receptors. To examine the effects of EGFR blockade on pancreatic cancer cell mitogenesis in relation to activation of specific signaling pathways, four pancreatic cancer cell lines were infected with an adenoviral vector encoding a truncated EGFR (AdtrEGFR), and activation of signaling was assessed with the mitogen-activated protein kinase (MAPK) kinase inhibitors PD98059 and U0126, the p38 MAPK inhibitor SB203580, and the c-Jun NH₂-terminal kinase inhibitor SP600125. In all four cell lines, AdtrEGFR markedly attenuated EGF and heparin-binding EGF-dependent cell growth, EGFR family tyrosine phosphorylation, and phosphorylation of MAPK, c-Jun NH₂-terminal kinase, p38 MAPK, and activating transcription factor 2. AdtrEGFR did not alter fibroblast growth factor 2 actions on mitogenesis. In ASPC-1, PANC-1, and T3M4 cells, PD98059 and U0126 inhibited MAPK kinase activation but not EGF-stimulated mitogenesis, whereas SB203580 inhibited EGF-stimulated mitogenesis, p38 MAPK activation, and MAPK-activated protein kinase 2 activation, without attenuating the mitogenic effect of insulin-like growth factor 1. In contrast, in COLO-357 cells, PD98059, and U0126, but not SB203580, inhibited EGF-stimulated mitogenesis, whereas SP600125 did not alter the mitogenic actions of EGF in any of the cell lines. Thus, EGF promotes proliferation via the MAPK in COLO-357 cells but via p38 MAPK in ASPC-1, PANC-1, and T3M4 cells, and whereas EGFR activation leads to the activation of all four members of the EGFR family in these cells, downstream signaling is efficiently blocked by AdtrEGFR.

This article has been cited by other articles:

				A. Matsushita, T. Gotze, and M. Korc Hepatocyte Growth Factor Mediated Cell Invasion in Pancreatic Cancer Cells Is Dependent on Neuropilin-1 Cancer Res., November 1, 2007; 67(21): 10309 - 10316. [Abstract] [Full Text] [PDF]

				G. Vlotides, M. Cruz-Soto, T. Rubinek, T. Eigler, C. J. Auernhammer, and S. Melmed Mechanisms for Growth Factor-Induced Pituitary Tumor Transforming Gene-1 Expression in Pituitary Folliculostellate TtT/GF Cells Mol. Endocrinol., December 1, 2006; 20(12): 3321 - 3335. [Abstract] [Full Text] [PDF]

				Z. Wang, R. Sengupta, S. Banerjee, Y. Li, Y. Zhang, K.M. W. Rahman, A. Aboukameel, R. Mohammad, A. P.N. Majumdar, J. L. Abbruzzese, et al. Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer. Cancer Res., August 1, 2006; 66(15): 7653 - 7660. [Abstract] [Full Text] [PDF]

				Y. Zhang, S. Banerjee, Z.-w. Wang, D. J. Marciniak, A. P.N. Majumdar, and F. H. Sarkar Epidermal Growth Factor Receptor-Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells Cancer Res., May 1, 2005; 65(9): 3877 - 3882. [Abstract] [Full Text] [PDF]

				J. K. Chan, H. Pham, X. J. You, N. G. Cloven, R. A. Burger, G. S. Rose, K. Van Nostrand, M. Korc, P. J. DiSaia, and H. Fan Suppression of Ovarian Cancer Cell Tumorigenicity and Evasion of Cisplatin Resistance Using a Truncated Epidermal Growth Factor Receptor in a Rat Model Cancer Res., April 15, 2005; 65(8): 3243 - 3248. [Abstract] [Full Text] [PDF]

				H. Xu, Y. Yu, D. Marciniak, A. K. Rishi, F. H. Sarkar, O. Kucuk, and A. P.N. Majumdar Epidermal growth factor receptor (EGFR)-related protein inhibits multiple members of the EGFR family in colon and breast cancer cells Mol. Cancer Ther., March 1, 2005; 4(3): 435 - 442. [Abstract] [Full Text] [PDF]

				J. Niu, Z. Li, B. Peng, and P. J. Chiao Identification of an Autoregulatory Feedback Pathway Involving Interleukin-1{alpha} in Induction of Constitutive NF-{kappa}B Activation in Pancreatic Cancer Cells J. Biol. Chem., April 16, 2004; 279(16): 16452 - 16462. [Abstract] [Full Text] [PDF]

				Y. Min, Y. Adachi, H. Yamamoto, H. Ito, F. Itoh, C.-T. Lee, S. Nadaf, D. P. Carbone, and K. Imai Genetic Blockade of the Insulin-like Growth Factor-I Receptor: A Promising Strategy for Human Pancreatic Cancer Cancer Res., October 1, 2003; 63(19): 6432 - 6441. [Abstract] [Full Text] [PDF]