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Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFα-mediated apoptosis

Cancer Gene Therapy volume 8, pages 897–905 (2001)Cite this article

Abstract

Lung cancer is the most frequently occurring cancer in the world and causes more deaths in the United States than does colon, breast, and prostate cancer combined. Despite advances in treatment modalities including radiation, surgery, and chemotherapy, the overall survival in lung cancer remains low. The cytokine tumor necrosis factor α (TNFα) has been shown to regulate both apoptotic and antiapoptotic pathways. Activation of the transcription factor NF-κB appears to be the critical determinant of the antiapoptotic response to TNFα exposure in epithelial cells. A549 human lung carcinoma cells were infected with adenoviral constructs carrying dominant negative mutants of Rac1 and IKK or constitutively active mutant of Rac1, upstream effectors in TNF-mediated NF-κB activation. Cell death, apoptosis, and NF-κB activation were subsequently measured in response to TNFα exposure. Although TNFα alone had no cytotoxic effect, the expression of the dominant negative mutant of IKKβ (Ad.IKKβKA) resulted in apoptotic cell death following TNFα exposure. Similarly, dominant negative mutant to Rac1 (Ad.N17Rac1) further sensitized A549 cells to IKKβKA-mediated TNFα-induced cell death. Conversely, a dominant active form of Rac1 (Ad.V12Rac1) ameliorated the cell death response to concurrent IKKβ dominant negative mutant infection and TNFα exposure. These results suggest that concurrent inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFα-induced apoptosis. Cancer Gene Therapy (2001) 8, 897–905

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Acknowledgements

We thank to Guoshun Wang and Paul B. McCray for the construction of Ad.NFκBLuc vector. Special thanks go to Ebrahim Zandi for providing us with IKKαKM and IKKβKA cDNA. This work was supported by the Center for Gene Therapy of Cystic Fibrosis and other Genetic Diseases cofunded by the National Institute of Health (P30 DK54759) and Cystic Fibrosis Foundation, and VA Merit Review Grant; NIH Grants ES-09607 and HL-60316 to G. W. Hunninghake.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Pulmonary, Critical Care, and Occupational Medicine, College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Salih Sanlioglu & Karl W Thomas

  2. The Center for Gene Therapy, College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Salih Sanlioglu

  3. Department of Medical Biology and Genetics, College of Medicine, Akdeniz University, Antalya, 07070, Turkey

    Salih Sanlioglu & Guven Luleci

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  1. Salih Sanlioglu
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Correspondence to Salih Sanlioglu.

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Sanlioglu, S., Luleci, G. & Thomas, K. Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFα-mediated apoptosis. Cancer Gene Ther 8, 897–905 (2001). https://doi.org/10.1038/sj.cgt.7700394

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