Oncogene Links Smoking Tobacco to Development of Non-Small-Cell Lung Cancer

The oncogene IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) was identified as a potential drug target in a recent study on the link between smoking tobacco and the development of non-small-cell lung cancer (NSCLC).

IKBKE is a member of the I-kappaB enzyme complex that is involved in propagating the cellular response to inflammation. This kinase enzyme complex is part of the upstream NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) signal transduction cascade.

Investigators at the Moffitt Cancer Center (Tampa, FL, USA) examined the role of IKBKE in tobacco-associated NSCLC. They reported in the January 10, 2013, online issue of the journal Oncogene that IKBKE was a downstream target of signal transducer and activator of transcription 3 (STAT3) and that tobacco components induced IKBKE expression through STAT3.

Stat3 is a member of the Stat protein family, which regulates many aspects of cell growth, survival, and differentiation. Malfunction of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that Stat proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. Constitutive Stat3 activation is associated with various human cancers and commonly suggests poor prognosis. It has antiapoptotic as well as proliferative effects.

The results of the current study revealed that expression of constitutively active STAT3 increased IKBKE mRNA and protein levels, whereas inhibition of STAT3 reduced IKBKE expression. Expression levels of IKBKE were significantly associated with STAT3 activation and tobacco use history in NSCLC patients examined. In addition, IKBKE expression was induced of by two components of cigarette smoke: nicotine and nicotine-derived nitrosamine ketone (NNK). Upon exposure to nicotine or NNK, cells expressed high levels of IKBKE protein and mRNA, and this activity could be blocked by inhibition of STAT3.

Enforced expression of IKBKE induced chemoresistance, whereas knockdown of IKBKE not only sensitized NSCLC cells to chemotherapy but also abrogated STAT3- and nicotine-induced cell survival.

“Since IKBKE kinase is induced by tobacco, small molecular inhibitors of IKBKE could have a therapeutic drug potential for lung cancer,” said senior author Dr. Jin Q. Cheng, a senior member of the molecular oncology department at the Moffitt Cancer Center. “Since the IKBKE kinase overexpression is induced by tobacco smoke and IKBKE levels increase in response to nicotine and nicotine-derived nitrosamine ketone, this evidence can be potentially used to develop a non-small-cell lung cancer intervention strategy that targets IKBKE.”

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Moffitt Cancer Center