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STAT3 regulated IKBKE in response to nicotine induced via tobacco carcinogen
Guo J. Oncogene. 2012. doi:10.1038/onc.2012.39.
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The immune response regulator IKBKE was observed to be a direct target of the STAT3 gene and tobacco components induced IKBKE expression through STAT3 in human non–small cell lung cancer, according to study results published in Oncogene.
Based on prior studies indicating that IKBKE (serine/theorinine/kinase) was overexpressed in primary breast and ovarian cancers, researchers from the Moffitt Cancer Center in Tampa, Fla. examined transcriptional regulation of IKBKE. As frequent activation of STAT3 had been observed in NSCLC, researchers investigated whether modulation of STAT3 would affect IKBKE expression.
“It has been well documented that STAT3 is activated by growth factors and environmental carcinogenesis, such as nicotine,” researcher Jin Q. Cheng, PhD, MD, said in a press release. “STAT3 directly binds to the IKBKE promoter and induces IKBKE transcription.”
According to the study results, IKBKE expression was stimulated 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 eliminated when STAT3 is inhibited. Analysis of the IKBKE promoter revealed that it bound directly to STAT3 and responded to nicotine and NNK stimulation.
“IKBKE is a newly identified oconogene, a gene linked to cancer,” Cheng said. “In our study, we demonstrated that IKBKE is a STAT3 target gene and is induced by tobacco. STAT3 is a signaling and transcription gene that is activated in various types of cancer and is required for cell transformation.”
Additionally, analysis revealed that enforcing expression of IKBKE fuels chemoresistance, whereas IKBKE depletion largely abolishes STAT3- and nicotine-induced cell survival and sensitizes NSCLC cells to chemotherapy. Researchers concluded that IKBKE is an important therapeutic target and could have a pivotal role in tobacco-associated lung carcinogenesis.
“Current treatments for non–small cell lung cancer include surgery, radiotherapy and chemotherapy,” Cheng said. “Advanced patients generally develop chemotherapy and radiotherapy resistance, so there is a great need to understand the molecular mechanism of therapy resistance in order to find ‘targets’ to overcome resistance.”
Disclosure: The researchers reported financial no relevant financial disclosures.
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