Targeting CREB Pathway Suppresses Small Cell Lung Cancer.
Targeting CREB Pathway Suppresses Small Cell Lung Cancer.
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靶向 CREB 通路抑制小细胞肺癌
DOI：
10.1158/1541-7786.mcr-17-0576
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发表时间：
2018-05
期刊：
影响因子：
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通讯作者：
Verma IM
中科院分区：
文献类型：
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作者：
Xia Y;Zhan C;Feng M;Leblanc M;Ke E;Yeddula N;Verma IM
小细胞肺癌（SCLC）是肺癌中最致命的亚型，因其预后不良。我们开发了一种慢病毒载体介导的小细胞肺癌小鼠模型，并探究了转录因子NF - κB和CREB家族在该模型中的作用。令人惊讶的是，在包括非小细胞肺癌（NSCLC）在内的许多癌症类型中促进肿瘤进展的NF - κB活性的诱导，在小细胞肺癌中却是不必要的。相反，抑制小细胞肺癌肿瘤中的NF - κB活性适度地加速了肿瘤发展。对小鼠和人类小细胞肺癌肿瘤的基因表达特征的检测显示，总体上NF - κB活性低但CREB活性高。通过蛋白激酶A的显性负性形式（dnPKA）阻断CREB激活完全消除了小细胞肺癌的发展。同样，dnPKA的表达或用蛋白激酶A抑制剂H89治疗在同基因移植模型中极大地减少了小细胞肺癌肿瘤的生长。总之，我们的结果强烈表明，靶向CREB是一种针对小细胞肺癌有前景的治疗策略。
Small cell lung cancer (SCLC) is the most deadly subtype of lung cancer due to its dismal prognosis. We have developed a lentiviral vector-mediated SCLC mouse model and have explored the role of both the NF-κB and CREB families of transcription factors in this model. Surprisingly, induction of NF-κB activity, which promotes tumor progression in many cancer types including non-small cell lung carcinoma (NSCLC), is dispensable in SCLC. Instead, suppression of NF-κB activity in SCLC tumors moderately accelerated tumor development. Examination of gene expression signatures of both mouse and human SCLC tumors revealed overall low NF-κB but high CREB activity. Blocking CREB activation by a dominant-negative form of PKA (dnPKA) completely abolished the development of SCLC. Similarly, expression of dnPKA or treatment with PKA inhibitor H89 greatly reduced the growth of SCLC tumors in syngeneic transplantation models. Altogether, our results strongly suggest that targeting CREB is a promising therapeutic strategy against SCLC.