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Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis

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Abstract

We have demonstrated that nuclear factor-κB (NF-κB) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-κB plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF-κB activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective IκBα (S32, 36A) (IκBαM) that blocks NF-κB activity. In this study, we showed that inhibiting constitutive NF-κB activity by expressing IκBαM suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-κB signaling by expressing IκBαM significantly reduced expression of Bcl-xL and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-κB signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-κB signaling pathway is a potential target for anticancer agents.

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Acknowledgements

We thank Mariann Crapanzano for editorial assistance. This work was supported in part by grants CA73675, CA78778, and CA 75517 from the National Cancer Institute (NCI), and a grant from the Lockton Fund for Pancreatic Cancer Research. WAF is a recipient of the NCI T32 Training Grant Fellowship, and GMS is a recipient of a Fellowship of the Cancer League of Bern, Switzerland.

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas, Houston, 77030, TX, USA

    Shuichi Fujioka, Guido M Sclabas, Christian Schmidt, Wayne A Frederick, Qiang G Dong, Douglas B Evans & Paul J Chiao

  2. The Graduate School of Biomedical Sciences, The University of Texas, Houston, 77030, TX, USA

    Jiangong Niu & Paul J Chiao

  3. Department of Gastrointestinal Medical Oncology, The University of Texas, Houston, 77030, TX, USA

    James L Abbruzzese

  4. Department of Cancer Biology, The University of Texas, Houston, 77030, TX, USA

    Cheryl Baker

  5. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, The University of Texas, Houston, 77030, TX, USA

    Paul J Chiao

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  1. Shuichi Fujioka
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  2. Guido M Sclabas
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  3. Christian Schmidt
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  4. Jiangong Niu
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  5. Wayne A Frederick
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  6. Qiang G Dong
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  7. James L Abbruzzese
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  8. Douglas B Evans
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  9. Cheryl Baker
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  10. Paul J Chiao
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Correspondence to Paul J Chiao.

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Fujioka, S., Sclabas, G., Schmidt, C. et al. Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis. Oncogene 22, 1365–1370 (2003). https://doi.org/10.1038/sj.onc.1206323

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  • DOI: https://doi.org/10.1038/sj.onc.1206323

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