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4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

Oncogene volume 30, pages 106–116 (2011)Cite this article

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Abstract

The role of thromboxane A2 (TxA2) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA2 synthase (TxAS) expression and thromboxane B2 (TxB2) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA2 synthesis and activates its receptor in lung cancer cells. The increased TxA2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.

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Acknowledgements

We thank Suk Ying Chun, Ernest Chi Wai Chak and Billy Cheuk Sing Leung for their technical assistance. This study was supported by the CUHK direct grants (2007.2.045 and 2008.2.038).

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Authors and Affiliations

  1. Department of Surgery, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    R-Y Huang, M-Y Li, M K Y Hsin, M J Underwood & G G Chen

  2. Department of Anatomic and Cellular Pathology, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    L T Ma

  3. Department of Clinical Oncology, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    T S K Mok

  4. The William Harvey Research Institute, Queen Mary University of London, London, UK

    T D Warner

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Huang, RY., Li, MY., Hsin, M. et al. 4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor. Oncogene 30, 106–116 (2011). https://doi.org/10.1038/onc.2010.390

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