Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor.
Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor.
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DOI：
10.1158/0008-5472.can-08-0280
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Brattain MG
中科院分区：
文献类型：
--
作者：
Hu YP;Patil SB;Panasiewicz M;Li W;Hauser J;Humphrey LE;Brattain MG
本研究确定了结肠癌细胞中IGF1R和EGFR之间的一种新的串扰模式。生长因子缺失细胞中IGF1R暴露激活诱导FET、CBS和GEO结肠癌细胞系中Akt激活。使用siRNA方法研究IGF1R介导的信号通路表明，正如预期的那样，PI3K被IGF1R激活。phospho-Erk诱导所反映的MAPK活性直到这些细胞从生长因子剥夺应激中释放后才被显著激活。phospho-Erk的出现与EGFR的激活密切相关。在释放应激之前用PI3K抑制剂LY294002处理细胞会导致EGFR激活的浓度依赖性丧失，而用MAPK抑制剂PD98059处理不会阻断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phospho-Erk的诱导，表明MAPK活性是EGFR介导的信号传导的结果。另一方面，IGF1R小分子抑制剂PQIP可阻断Akt磷酸化。IGF1R和EGFR不同的信号功能表明，针对这两种受体的联合治疗可能具有协同作用。通过联合指数分析，PQIP和EGFR抑制剂特罗凯联合治疗在所有3个细胞系中均产生协同效应。
This study identifies a novel crosstalk paradigm between the IGF1R and 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 siRNA approaches indicated that, as expected, PI3K was activated by IGF1R. MAPK activity as reflected by phospho-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 prior to release from stress resulted in a concentration dependent loss of EGFR activation while 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 2 receptors. Combination treatment with PQIP and EGFR inhibitor Tarceva resulted in synergistic effects as indicated by combination index analysis in all 3 cell lines tested.