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Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis

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Abstract

Since the NF-κB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-κB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated IκBα (IκBαM), which blocks NF-κB activity. Parental (PC-3M), control vector-transfected (PC-3M-Neo), and IκBαM-transfected (PC-3M–IκBαM) cells were injected into the prostate gland of nude mice. PC-3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M–IκBαM cells produced slow growing tumors with low metastatic potential. NF-κB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis. Inhibition of NF-κB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF-κB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.

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Acknowledgements

We thank Dr P Chiao (Department of Surgical Oncology) for pLXSN–IκBαM, Dr B Su (Department of Immunology) for 2x NF-κB reporter constructs, Dr D Boyd (Department of Cancer Biology) for the pGL2–MMP-9 reporter, Dr K Xie (Department of Gastrointestinal Medical Oncology) for the pGL2–VEGF reporter, and Drs N Mukaida and K Matsushima (Kanazawa University, Kanazawa, Japan) for the pxp2-IL8-1481 promoter. This work was supported in part by Cancer Center Support Core grant CA16672 and grant R35-CA42107 (IJ Fidler) from the National Cancer Institute, National Institutes of Health. The authors are grateful to Walter Pagel for his critical editorial comments, and Vallery Bolden-Hill for expert assistance in the preparation of this manuscript.

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  1. Department of Cancer Biology, Box 173, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Suyun Huang, Curtis A Pettaway, Hisanori Uehara, Corazon D Bucana & Isaiah J Fidler

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  1. Suyun Huang
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  2. Curtis A Pettaway
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  3. Hisanori Uehara
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  4. Corazon D Bucana
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  5. Isaiah J Fidler
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Correspondence to Isaiah J Fidler.

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Huang, S., Pettaway, C., Uehara, H. et al. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001). https://doi.org/10.1038/sj.onc.1204535

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  • DOI: https://doi.org/10.1038/sj.onc.1204535

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