Src-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines
Src-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines
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DOI：
10.2353/ajpath.2007.060706
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发表时间：
2007-01-01
影响因子：
6
通讯作者：
Kurie, Jonathan M.
中科院分区：
文献类型：
--
作者：
Zhang, Jie;Kalyankrishna, Shailaja;Kurie, Jonathan M.
Src家族激酶（SFKs）在非小细胞肺癌（NSCLC）中的作用尚未完全确定。在这里，我们解决了这个问题，通过检查SFK磷酸化在非小细胞肺癌活检样本，并使用遗传和药理学的方法来抑制SFK的表达和活性在培养的非小细胞肺癌细胞。使用Tyr 416磷酸化特异性泛SFK抗体对NSCLC活检样本进行免疫组织化学分析，发现370个肿瘤中有123个（33%）染色。由于c-Src是已知的表皮生长因子受体（EGFR）的上游激活剂和下游介质，我们接下来研究了一组NSCLC细胞系中的SFK磷酸化，包括依赖EGFR生存的细胞系。EGFR依赖性NSCLC细胞系HCC 827和H3255具有增加的SFK磷酸化，并且用SFK抑制剂（PP 1或SKI-606）处理这些细胞诱导凋亡。PP 1降低EGFR、ErbB 2和ErbB 3的磷酸化，并显著增强EGFR抑制剂吉非替尼引起的细胞凋亡。用c-Src短发夹RNA转染的HCC 827细胞表现出EGFR和ErbB 2磷酸化减少，并且对PP 1或吉非替尼的凋亡敏感性降低。我们的结论是SFKs在NSCLC活检样本中被激活，促进EGFR依赖性NSCLC细胞的存活，并且应该作为NSCLC患者的治疗靶点进行研究。
The role of Src-family kinases (SFKs) in non-small cell lung cancer (NSCLC) has not been fully defined. Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells. Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation-specific, pan-SFK antibody revealed staining in 123 (33%) of 370 tumors. Because c-Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor (EGFR), we next investigated SFK phosphorylation in a panel of NSCLC cell lines, including ones that depend on EGFR for survival. The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis. PP1 decreased phosphorylation of EGFR, ErbB2, and ErbB3 and strikingly enhanced apoptosis by gefitinib, an EGFR inhibitor. HCC827 cells transfected with c-Src short hairpin RNA exhibited diminished phosphorylation of EGFR and ErbB2 and decreased sensitivity to apoptosis by PP1 or gefitinib. We conclude that SFKs are activated in NSCLC biopsy samples, promote the survival of EGFR-dependent NSCLC cells, and should be investigated as therapeutic targets in NSCLC patients.