Sprouty2 protein enhances the response to gefitinib through epidermal growth factor receptor in colon cancer cells
Sprouty2 protein enhances the response to gefitinib through epidermal growth factor receptor in colon cancer cells
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DOI：
10.1111/j.1349-7006.2010.01637.x
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发表时间：
2010-09-01
期刊：
影响因子：
5.7
通讯作者：
Lee, Jeng-Chang
中科院分区：
文献类型：
--
作者：
Feng, Yin-Hsun;Tsao, Chao-Jung;Lee, Jeng-Chang
已知Sprouty 2（Spry 2）通过与c-Casitas B系淋巴瘤（C-Cbl）缀合以减少蛋白质降解来增加表皮生长因子受体（EGFR）的表达。Spry 2对吉非替尼（一种EGFR酪氨酸激酶抑制剂）治疗结肠癌的效果尚不清楚。评估了吉非替尼在6种结肠癌细胞系中的半数最大抑制浓度（IC 50）值。HCT 116和C2BBel细胞表达较低水平的Spry 2蛋白，对吉非替尼的敏感性较低，而表达高水平Spry 2蛋白的HT 29细胞对吉非替尼的敏感性更高。在HCT 116细胞中过表达Spry 2后，对吉非替尼的敏感性增加，而在HT 29细胞中敲低Spry 2后，对吉非替尼的敏感性降低。当HCT 116细胞异位过表达Spry 2时，磷酸化EGFR和总EGFR的水平均增加，同时磷酸酶和张力蛋白同源物（PTEN）表达增加。西妥昔单抗抑制EGFR可降低过表达Spry 2的HCT 116细胞对吉非替尼的敏感性。然而，敲除PTEN或K-ras未能减弱Spry 2对吉非替尼敏感性的影响。值得注意的是，Spry 2增强了吉非替尼在HCT 116肿瘤异种移植模型中的抗肿瘤作用，该模型具有K-ras密码子13突变。综上所述，Spry 2可通过增加磷酸化EGFR和总EGFR的表达来增强结肠癌细胞对吉非替尼的反应。这些结果表明，Spry 2可能是预测结肠癌抗EGFR治疗反应的潜在生物标志物，并且有必要进行临床研究以将Spry 2纳入癌症治疗网络。（Cancer Sci 2010）。
Sprouty2 (Spry2) is known to increase the expression of epidermal growth factor receptors (EGFR) by conjugating with c-Casitas B-lineage lymphoma (C-Cbl) to decrease protein degradation. The effect of Spry2 on the treatment of gefitinib, a tyrosine kinase inhibitor of EGFR, with regards to colon cancer is still unclear. The half maximal inhibitory concentration (IC50) values of gefitinib in six colon cancer cell lines were assessed. HCT116 and C2BBel cells expressed lower levels of Spry2 protein and were less sensitive to gefitinib, whereas HT29 cells that expressed high levels of Spry2 protein were more sensitive to gefitinib. The sensitivity to gefitinib was increased after overexpression of Spry2 in HCT116 cells, whereas it was decreased after Spry2 knockdown in HT29 cells. The levels of both phosphorylated and total EGFR were increased when HCT116 cells ectopically overexpressed Spry2, with concomitant increase in phosphatase and tensin homolog (PTEN) expression. Inhibition of EGFR by cetuximab reduced sensitivity to gefitinib in HCT116 cells overexpressing Spry2. However, knockdown of PTEN or K-ras failed to diminish the effect of Spry2 on gefitinib sensitivity. Of note, Spry2 enhanced the antitumor effect of gefitinib in a xenograft model of HCT116 tumors, which harbored K-ras codon 13 mutation. In conclusion, Spry2 can enhance the response of colon cancer cells to gefitinib by increasing the expression of phosphorylated and total EGFR. These results suggest that Spry2 may be a potential biomarker in predicting the response to anti-EGFR treatment in colon cancer and that it is necessary to conduct clinical studies to incorporate Spry2 into the network of cancer treatment. (Cancer Sci 2010).