Hu Yi Peter, Patil Sandip B, Panasiewicz Michelle, Li Wenhui, Hauser Jennie, Humphrey Lisa E, Brattain Michael G
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA.
Cancer Res. 2008 Oct 1;68(19):8004-13. doi: 10.1158/0008-5472.CAN-08-0280.
This study identifies a novel cross-talk paradigm between the type I insulin-like growth factor receptor (IGF1R) and epidermal growth factor receptor (EGFR) in colon cancer cells. IGF1R activation by ligand exposure in growth factor-deprived cells induces Akt activation in the FET, CBS, and GEO colon cancer cell lines. Investigation of IGF1R-mediated signaling pathways using small interfering RNA approaches indicated that, as expected, phosphatidylinositol 3'-kinase (PI3K) was activated by IGF1R. Mitogen-activated protein kinase (MAPK) activity as reflected by phospho-extracellular signal-regulated kinase (ERK) induction was not significantly activated until later times following release of these cells from growth factor deprivation stress. The appearance of phospho-ERK was proximal to EGFR activation. Treatment of cells with the PI3K inhibitor LY294002 before release from stress resulted in a concentration-dependent loss of EGFR activation, whereas treatment with the MAPK inhibitor PD98059 did not block EGFR activation, indicating that EGFR activation was downstream of the IGF1R/PI3K pathway. PD98059 inhibition of MAPK was associated with a concentration-dependent reduction in EGFR-mediated phospho-ERK. EGFR inhibitor blocked induction of phospho-ERK, showing that MAPK activity was a consequence of EGFR-mediated signaling. On the other hand, a small-molecule IGF1R inhibitor, PQIP, blocked Akt phosphorylation. The divergent signaling functions of IGF1R and EGFR suggested the potential for synergism by a combination of therapy directed at the two receptors. Combination treatment with PQIP and EGFR inhibitor Tarceva resulted in synergistic effects as indicated by combination index analysis in all three cell lines tested.
本研究确定了结肠癌细胞中I型胰岛素样生长因子受体（IGF1R）与表皮生长因子受体（EGFR）之间一种新的相互作用模式。在生长因子缺乏的细胞中，通过配体暴露激活IGF1R可诱导FET、CBS和GEO结肠癌细胞系中的Akt激活。使用小分子干扰RNA方法对IGF1R介导的信号通路进行研究表明，正如预期的那样，磷脂酰肌醇3'-激酶（PI3K）被IGF1R激活。在这些细胞从生长因子剥夺应激中释放后的较晚时间，有丝分裂原激活蛋白激酶（MAPK）活性（通过磷酸化细胞外信号调节激酶（ERK）的诱导反映）才被显著激活。磷酸化ERK的出现靠近EGFR激活。在从应激中释放之前，用PI3K抑制剂LY294002处理细胞会导致EGFR激活呈浓度依赖性丧失，而用MAPK抑制剂PD98059处理则不会阻断EGFR激活，这表明EGFR激活位于IGF1R/PI3K途径的下游。PD98059对MAPK的抑制与EGFR介导的磷酸化ERK的浓度依赖性降低有关。EGFR抑制剂阻断了磷酸化ERK的诱导，表明MAPK活性是EGFR介导信号传导的结果。另一方面，小分子IGF1R抑制剂PQIP阻断了Akt磷酸化。IGF1R和EGFR不同的信号功能提示了针对这两种受体的联合治疗具有协同作用的潜力。在所有测试的三种细胞系中，通过联合指数分析表明，PQIP与EGFR抑制剂特罗凯联合治疗产生了协同效应。
