*Medical Research Center, †Department of Internal Medicine, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan; ‡Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; §Department of Medical Research, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; ‖National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; ¶Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; #Department of Pathology, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan; **Department of Emergency Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; ††Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan; and ‡‡Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
J Thorac Oncol. 2014 Apr;9(4):488-96. doi: 10.1097/JTO.0000000000000107.
Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor that modulates survival-directed transcription, is often persistently activated in epidermal growth factor receptor (EGFR) wild-type non-small-cell lung cancer (NSCLC). The aim of this study was to determine whether sorafenib and its derivative can inhibit EGFR wild-type NSCLC via STAT3 inactivation.
EGFR wild-type NSCLC cell lines (A549 H292 H322 H358 and H460) were treated with sorafenib or SC-1, a sorafenib derivative that closely resembled sorafenib structurally but was devoid of kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 and A549 xenograft.
SC-1 had better effects than sorafenib on growth inhibition and apoptosis in all tested EGFR wild-type NSCLC lines. SC-1 reduced STAT3 phosphorylation at tyrosine 705 in all tested EGFR wild-type NSCLC cells. The expression of STAT3-driven genes, including cylcin D1 and survivin, was also repressed by SC-1. Ectopic expression of STAT3 in H460 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 enhanced Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) activity, whereas knockdown of SHP-1, but not SHP-2 or protein-tyrosine phosphatase 1B (PTP-1B), by small interference RNA reduced SC-1-induced apoptosis. SC-1 significantly reduced H460 and A549 tumor growth in vivo through SHP-1/STAT3 pathway.
SC-1 provides proof that targeting STAT3 signaling pathway may be a novel approach for the treatment of EGFR wild-type NSCLC.
信号转导子和转录激活子 3（STAT3）是一种调节生存导向转录的转录因子，在表皮生长因子受体（EGFR）野生型非小细胞肺癌（NSCLC）中常持续激活。本研究旨在确定索拉非尼及其衍生物是否可以通过 STAT3 失活抑制 EGFR 野生型 NSCLC。
用索拉非尼或索拉非尼衍生物 SC-1 处理 EGFR 野生型 NSCLC 细胞系（A549、H292、H322、H358 和 H460）。分析凋亡和信号转导。在裸鼠 H460 和 A549 异种移植模型中评估体内疗效。
SC-1 对所有测试的 EGFR 野生型 NSCLC 株的生长抑制和凋亡作用均优于索拉非尼。SC-1 降低了所有测试的 EGFR 野生型 NSCLC 细胞中 STAT3 酪氨酸 705 的磷酸化。STAT3 驱动基因的表达，包括 cyclin D1 和 survivin，也被 SC-1 抑制。STAT3 在外源表达的 H460 细胞中，SC-1 处理的细胞凋亡被消除。索拉非尼和 SC-1 通过 Src 同源-2 含蛋白酪氨酸磷酸酶-1（SHP-1）增强活性，而 SHP-1 敲低，而非 SHP-2 或蛋白酪氨酸磷酸酶 1B（PTP-1B）的小干扰 RNA 降低了 SC-1 诱导的凋亡。SC-1 通过 SHP-1/STAT3 通路显著减少了体内 H460 和 A549 肿瘤的生长。
SC-1 为靶向 STAT3 信号通路治疗 EGFR 野生型 NSCLC 提供了证据。
