Matsuda Kei, Idezawa Takenao, You Xue Juan, Kothari Nayantara H, Fan Hung, Korc Murray
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of California, Irvine, California 92697, USA.
Cancer Res. 2002 Oct 1;62(19):5611-7.
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.
表皮生长因子（EGF）受体（EGFR）家族由四种跨膜酪氨酸激酶组成，这些激酶可发生同源二聚化和异源二聚化。胰腺癌中这些受体过度表达。为了研究EGFR阻断对胰腺癌细胞有丝分裂的影响以及与特定信号通路激活的关系，用编码截短型EGFR的腺病毒载体（AdtrEGFR）感染四种胰腺癌细胞系，并用丝裂原活化蛋白激酶（MAPK）激酶抑制剂PD98059和U0126、p38 MAPK抑制剂SB203580以及c-Jun NH2末端激酶抑制剂SP600125评估信号通路的激活情况。在所有四种细胞系中，AdtrEGFR均显著减弱了EGF和肝素结合型EGF依赖的细胞生长、EGFR家族酪氨酸磷酸化以及MAPK、c-Jun NH2末端激酶、p38 MAPK和激活转录因子2的磷酸化。AdtrEGFR并未改变成纤维细胞生长因子2对有丝分裂的作用。在ASPC-1、PANC-1和T3M4细胞中，PD98059和U0126抑制了MAPK激酶激活，但未抑制EGF刺激的有丝分裂，而SB203580抑制了EGF刺激的有丝分裂、p38 MAPK激活以及MAPK激活的蛋白激酶2激活，且未减弱胰岛素样生长因子1的促有丝分裂作用。相比之下，在COLO-357细胞中，PD98059和U0126抑制了EGF刺激的有丝分裂，但SB203580未起作用，而SP600125在任何细胞系中均未改变EGF的促有丝分裂作用。因此，在COLO-357细胞中EGF通过MAPK促进增殖，而在ASPC-1、PANC-1和T3M4细胞中通过p38 MAPK促进增殖，并且尽管EGFR激活导致这些细胞中EGFR家族的所有四个成员被激活，但AdtrEGFR有效地阻断了下游信号传导。
