Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells
Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells
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阻断sonic hedgehog信号通路增强EGFR抑制剂对胰腺癌细胞的抗增殖作用
DOI：
10.1111/j.1745-7254.2007.00620.x
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发表时间：
2007-08-01
影响因子：
8.2
通讯作者：
Wang, Chun-you
中科院分区：
文献类型：
--
作者：
Hu, Wei-guo;Liu, Tao;Wang, Chun-you
目的：研究胰腺癌细胞中音刺猬（SHH）和表皮生长因子受体（EGFR）信号分子的表达，并评估环巴胺和易瑞沙分别通过阻断SHH和EGFR信号通路的抑制作用。方法：采用RT-PCR和Western blot方法检测胰腺癌细胞株PANC-1、SUIT-2和ASPC-1中SHH和EGFR的表达。用不同浓度的环巴胺单独或与易瑞沙组合处理后，通过甲基噻唑基四唑测定分析对胰腺癌细胞的抗增殖作用。流式细胞仪检测胰腺癌细胞周期分布及凋亡情况。结果：3种胰腺癌细胞系均表达SHH、Smoothened（SMO）和EGFR。环巴胺可下调EGFR在所有细胞系中的表达。环巴胺或易瑞沙均能剂量依赖性地诱导生长抑制作用。此外，2.5 μ mol/L环巴胺和1 μ mol/L易瑞沙联合使用诱导的抑制作用增强，细胞凋亡率高于单独使用任何药物。随着环巴胺和/或易瑞沙剂量的增加，G（0）/G（1）和亚G（1）期细胞群的百分比沿着显著增加。结论：阻断Sonic Hedgehog信号通路可通过下调EGFR抑制剂在胰腺癌细胞中的表达增强EGFR抑制剂的抗增殖作用。SHH和EGFR信号的同时阻断代表了胰腺癌新治疗策略的可能靶点。
Aim: To investigate the expression of sonic hedgehog (SHH) and epidermal growth factor receptor (EGFR) signal molecules in pancreatic cancer cells, and to assess the inhibitory effects through the blockade of the SHH and EGFR signaling pathways by cyclopamine and Iressa, respectively. Methods: The expression of SHH and EGFR in pancreatic cancer cell lines (PANC-1, SUIT-2, and ASPC-1) was detected by RT-PCR and Western blot analysis. After treatment with different concentrations of cyclopamine, alone or in combination with Iressa, the antiproliferative effect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazolium assays. A flow cytometry analysis was used to detect the cellular cycle distribution and apoptosis of pancreatic cancer cells. Results: All of the 3 pancreatic cancer cell lines expressed SHH, Smoothened (SMO), and EGFR. Cyclopamine could downregulate the expression of EGFR in all cell lines. Cyclopamine or Iressa could induce a growth inhibitory effect in a dose-dependent manner. Moreover, the combined use of 2.5 mu mol/L cyclopamine and 1 mu mol/L Iressa induced an enhanced inhibitory effect and a greater apoptosis rate than any agent alone. The percentage of the cell population of the G(0)/G(1) and sub-G(1) phases was significantly increased along with the increasing dose of cyclopamine and/or Iressa. Conclusion:The blockade of the sonic hedgehog signal pathway enhances the antiproliferative effect of the EGFR inhibitor through the downregulation of its expression in pancreatic cancer cells. The simultaneous blockade of SHH and EGFR signaling represents possible targets of new treatment strategies for pancreatic carcinoma.