Tyrphostin AG1478 suppresses proliferation and invasion of human breast cancer cells.
Tyrphostin AG1478 suppresses proliferation and invasion of human breast cancer cells.
复制标题
DOI：
10.3892/ijo_00000045
复制
发表时间：
2008
影响因子：
5.2
通讯作者：
Yun-gang Zhang;Q. Du;W. Fang;M. Jin;X. Tian
中科院分区：
文献类型：
--
作者：
Yun-gang Zhang;Q. Du;W. Fang;M. Jin;X. Tian
抑制表皮生长因子受体（EGFR）信号是一种很有前景的恶性肿瘤治疗策略。在这项研究中，我们评估了一种有效的特异性EGFR酪氨酸激酶抑制剂tyrphostin AG1478对乳腺癌细胞生长、凋亡和侵袭的影响。Western blotting结果显示，AG1478抑制EGFR、ERK1/2和AKT的磷酸化呈剂量依赖性。三个增殖分析，MTT，细胞计数和克隆形成实验一致显示AG1478以剂量依赖性方式显著抑制细胞增殖。FACS分析显示AG1478促进细胞凋亡。此外，TRAP实验显示AG1478显著抑制肿瘤细胞端粒酶活性，与生长抑制平行。半定量RT-PCR结果显示，端粒酶活性的抑制与人类端粒酶催化亚单位（hTERT） mRNA表达的降低有关，后者是端粒酶活性的限制性决定因素。这些数据表明，AG1478通过抑制细胞增殖、诱导细胞凋亡和抑制端粒酶活性来抑制细胞生长。此外，我们还研究了AG1478对细胞侵袭的影响。Boyden室侵袭实验显示，AG1478对细胞侵袭有明显的抑制作用，且呈剂量依赖性。Western blotting结果显示，AG1478可下调MMP-9的表达，这可能是AG1478抑制细胞侵袭的机制之一。综上所述，本研究表明Tyrphostin AG1478能有效抑制乳腺癌细胞的增殖和侵袭。Tyrphostin AG1478可能是一种潜在的egfr靶向乳腺癌治疗剂。
Inhibition of epidermal growth factor receptor (EGFR) signaling is a promising treatment strategy for malignant tumors. In this study, we evaluated the effectiveness of tyrphostin AG1478, a potent and specific inhibitor of EGFR tyrosine kinase, on the growth, apoptosis and invasion of breast cancer cells. Western blotting demonstrated that AG1478 inhibited the phosphorylation of EGFR, ERK1/2 and AKT in a dose-dependent manner. Three proliferation analyses, MTT, cell counting, and clone formation assay, consistently showed that AG1478 significantly inhibited cell proliferation in a dose-dependent manner. FACS analysis demonstrated that AG1478 promoted cell apoptosis. In addition, TRAP assay exhibited that AG1478 significantly suppressed telomerase activity of tumor cells, which was parallel with growth inhibition. Semi-qantitative RT-PCR revealed that the suppression of telomerase activity was correlated with the decreased expression of human telomerase catalytic subunit (hTERT) mRNA, the rate-limiting determinant of its enzyme activity. These data suggest that AG1478 suppressed cellular growth by inhibiting cellular proliferation, inducing apoptosis and inhibiting telomerase activity. Furthermore, we also examined the effects of AG1478 on cellular invasion. Boyden chamber invasion assay showed that AG1478 significantly inhibited cell invasion in a dose-dependent manner. Western blotting revealed that AG1478 could down-regulate the expression of MMP-9, which may be one of the mechanisms by which AG1478 suppressed cellular invasion. In conclusion, this study demonstrated that Tyrphostin AG1478 effectively inhibited the proliferation and invasion of breast cancer cells. Tyrphostin AG1478 may be a potential EGFR-targeted therapeutic agent for breast cancer.