Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells.
Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells.
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DOI：
10.1016/j.peptides.2017.01.012
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发表时间：
2017-04
期刊：
影响因子：
3
通讯作者：
Jensen RT
中科院分区：
文献类型：
--
作者：
Moody TW;Ramos-Alvarez I;Moreno P;Mantey SA;Ridnour L;Wink D;Jensen RT
内皮素（ET）-1是一种重要的多肽，在肿瘤的发展过程中刺激细胞增殖，肿瘤血管生成和转移。ET-1以高亲和力结合癌细胞上的ETA受体（R）和ETBR。高水平的肿瘤ET-1和ETAR与肺癌患者的生存率低相关。在这里，使用非小细胞肺癌（NSCLC）细胞研究了ET-1对表皮生长因子（EGF）R和HER 2反式激活的影响。ETAR mRNA在所有10个NSCLC细胞系中均存在。向NCI-H838或H1975细胞中加入ET-1在2分钟内增加EGFR、HER 2和ERK酪氨酸磷酸化。拉帕替尼可抑制向NSCLC细胞中加入ET-1引起的EGFR和HER 2反式激活的增加（EGFR和HER 2酪氨酸激酶抑制剂（TKI）），吉非替尼（EGFR TKI）、ZD 4054或BQ-123（ETAR拮抗剂）、GM 6001（基质金属蛋白酶抑制剂）、PP 2（Src抑制剂）或Tiron（超氧化物清除剂）。ET-1增加NSCLC细胞胞浆Ca ~（2+）和活性氧。ET-1增加NSCLC克隆生长，而BQ 123、ZD 4054、拉帕替尼或吉非替尼抑制增殖。结果表明，ET-1可能以EGFR和HER 2依赖的方式调节NSCLC细胞的增殖。
Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2 min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR-and HER2-dependent manner.