Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer.
Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer.
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DOI：
10.1016/j.lungcan.2015.09.014
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Tweardy DJ
中科院分区：
文献类型：
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作者：
Lewis KM;Bharadwaj U;Eckols TK;Kolosov M;Kasembeli MM;Fridley C;Siller R;Tweardy DJ
肺癌是男性和女性癌症死亡的主要原因。非小细胞肺癌（NSCLC）的总体5年生存率为15%。虽然先前在NSCLC中观察到异常STAT 3激活，但其作用范围尚不确定，并且临床上没有靶向STAT 3治疗的药物。我们测定了8种NSCLC细胞系蛋白提取物中活化的STAT 3（在Y 705上磷酸化的STAT 3，pSTAT 3）和STAT 3的两种主要亚型（α和β）的水平，以及使用短发夹（sh）RNA和两种新型小分子STAT 3抑制剂C188-9和piperlongumine（PL）在NSCLC细胞中体外和体内靶向STAT 3的作用。在8个NSCLC细胞系中，7个细胞系的pSTAT 3、STAT 3 α和STATβ水平升高。值得注意的是，pSTAT 3的水平与STAT 3 β的水平密切相关，但与STAT 3 α无关。使用shRNA靶向A549细胞中的STAT 3使tSTAT 3降低75%;这伴随着锚定依赖性和锚定非依赖性生长降低47-78%，并且抗凋亡STAT 3基因靶点的mRNA水平降低28-45%。C188-9和PL（@30μM）均使所有检测的NSCLC细胞系中的pSTAT 3水平降低≥ 50%，使抗凋亡蛋白mRNA水平降低25- 60%，并降低NSCLC细胞系的锚定依赖性和锚定非依赖性生长，IC 50值分别为3.06-52.44μM和0.86-11.66μM。用C188-9或PL治疗携带A549肿瘤异种移植物的裸鼠阻断肿瘤生长并降低pSTAT 3和编码抗凋亡蛋白的mRNA的水平。STAT 3对NSCLC细胞系和肿瘤的生长至关重要，使用C188-9或PL靶向其可能是一种有用的治疗策略。
Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically. We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and β) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL). Levels of pSTAT3, STAT3α, and STATβ were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3β, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47–78% reduction in anchorage-dependent and anchorage-independent growth and a 28–45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30μM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25–60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06–52.44μM and 0.86–11.66μM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins. STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment.