Department of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Oncogene. 2013 Jan 10;32(2):151-9. doi: 10.1038/onc.2012.39. Epub 2012 Feb 13.
Serine/threonine kinase IKBKE is a newly identified oncogene; however, its regulation remains elusive. Here, we provide evidence that IKBKE is a downstream target of signal transducer and activator of transcription 3 (STAT3) and that tobacco components induce IKBKE expression through STAT3. Ectopic expression of constitutively active STAT3 increased IKBKE mRNA and protein levels, whereas inhibition of STAT3 reduced IKBKE expression. Furthermore, expression levels of IKBKE are significantly associated with STAT3 activation and tobacco use history in non-small cell lung cancer (NSCLC) patients examined. In addition, we show induction of IKBKE by two components of cigarette smoke, nicotine and nicotine-derived nitrosamine ketone (NNK). Upon exposure to nicotine or NNK, cells express high levels of IKBKE protein and mRNA, which are largely abrogated by inhibition of STAT3. Characterization of the IKBKE promoter revealed two STAT3-response elements. The IKBKE promoter directly bound to STAT3 and responded to nicotine and NNK stimulation. Notably, enforcing expression of IKBKE induces chemoresistance, whereas knockdown of IKBKE not only sensitizes NSCLC cells to chemotherapy but also abrogates STAT3- and nicotine-induced cell survival. These data indicate for the first time that IKBKE is a direct target of STAT3 and is induced by tobacco carcinogens through STAT3 pathway. In addition, our study also suggests that IKBKE is an important therapeutic target and could have a pivotal role in tobacco-associated lung carcinogenesis.
丝氨酸/苏氨酸激酶 IKBKE 是一种新鉴定的癌基因；然而，其调控机制仍不清楚。在这里，我们提供的证据表明 IKBKE 是信号转导和转录激活因子 3（STAT3）的下游靶标，烟草成分通过 STAT3 诱导 IKBKE 的表达。组成型激活 STAT3 的异位表达增加了 IKBKE mRNA 和蛋白水平，而 STAT3 的抑制降低了 IKBKE 的表达。此外，在非小细胞肺癌（NSCLC）患者中，IKBKE 的表达水平与 STAT3 激活和吸烟史显著相关。此外，我们还展示了香烟中的两种成分尼古丁和尼古丁衍生的亚硝胺酮（NNK）诱导 IKBKE 的情况。暴露于尼古丁或 NNK 后，细胞表达高水平的 IKBKE 蛋白和 mRNA，而 STAT3 的抑制大大降低了其表达。IKBKE 启动子的特征分析揭示了两个 STAT3 反应元件。IKBKE 启动子直接与 STAT3 结合，并对尼古丁和 NNK 刺激作出反应。值得注意的是，强制表达 IKBKE 会诱导化疗耐药性，而 IKBKE 的敲低不仅使 NSCLC 细胞对化疗更敏感，而且还消除了 STAT3 和尼古丁诱导的细胞存活。这些数据首次表明 IKBKE 是 STAT3 的直接靶标，并通过 STAT3 途径被烟草致癌物诱导。此外，我们的研究还表明，IKBKE 是一个重要的治疗靶点，并可能在烟草相关的肺癌发生中起关键作用。
