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RETRACTED ARTICLE: IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer

Oncogene volume 32, pages 151–159 (2013)Cite this article

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This article was retracted on 05 March 2024

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Abstract

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.

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Acknowledgements

We are grateful to Tissue Procurement, DNA Sequence and Image Core Facilities at H Lee Moffitt Cancer Center for providing cancer specimens, sequencing and cell apoptosis analysis as well as Fumi Kinose for helping provide lung cancer cell lines from the Moffitt lung cancer cell line core. This work was supported by NCI Grants CA137041 (JQC) and P50 CA119997 (EBH) and James and Esther King Biomedical Research Program 1KG02 (JQC), 1KD04 (JG) and 1KN08 (DK).

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Authors and Affiliations

  1. Department of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA

    J Guo, D Kim, J Gao, C Kurtyka, H Chen, C Yu, D Wu, A Mittal & J Q Cheng

  2. Department of Immunology, H Lee Moffitt Cancer Center, Tampa, FL, USA

    A A Beg

  3. Department of Tumor Biology, H Lee Moffitt Cancer Center, Tampa, FL, USA

    S P Chellappan

  4. Department of Thoracic Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA

    E B Haura

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Correspondence to J Q Cheng.

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Guo, J., Kim, D., Gao, J. et al. RETRACTED ARTICLE: IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer. Oncogene 32, 151–159 (2013). https://doi.org/10.1038/onc.2012.39

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