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Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

Oncogene volume 24, pages 4486–4495 (2005)Cite this article

Abstract

Recent studies indicate that natural isothiocyanates, such as sulforaphane (SFN) and phenethyl isothiocyanate (PEITC) possess strong antitumor activities in vitro and in vivo. The nuclear factor kappa B (NF-κB) is believed to play an important role in cancer chemoprevention due to its involvement in tumor cell growth, proliferation, angiogenesis, invasion, apoptosis, and survival. In this study, we investigated the effects and the molecular mechanisms of SFN and PEITC on NF-κB transcriptional activation and NF-κB-regulated gene expression in human prostate cancer PC-3 C4 cells. Treatment with SFN (20 and 30 μ M) and PEITC (5 and 7.5 μ M) significantly inhibited NF-κB transcriptional activity, nuclear transloction of p65, and gene expression of NF-κB-regulated VEGF, cylcin D1, and Bcl-XL in PC-3 C4 cells. To further elucidate the mechanism, we utilized the dominant-negative mutant of inhibitor of NF-κB alpha (IκBα) (SR-IκBα). Analogous to treatments with SFN and PEITC, SR-IκBα also strongly inhibited NF-κB transcriptional activity as well as VEGF, cylcin D1, and Bcl-XL expression. Furthermore, SFN and PEITC also inhibited the basal and UVC-induced phosphorylation of IκBα and blocked UVC-induced IκBα degradation in PC-3 C4 cells. In examining the upstream signaling, we found that the dominant-negative mutant of IKKβ (dnIKKβ) possessed inhibitory effects similar to SFN and PEITC on NF-κB, VEGF, cylcin D1, Bcl-XL as well as IκBα phosphorylation. In addition, treatment with SFN and PEITC potently inhibited phosphorylation of both IKKβ and IKKα and significantly inhibited the in vitro phosphorylation of IκBα mediated by IKKβ. Taken together, these results suggest that the inhibition of SFN and PEITC on NF-κB transcriptional activation as well as NF-κB-regulated VEGF, cyclin D1, and Bcl-XL gene expression is mainly mediated through the inhibition of IKK phosphorylation, particularly IKKβ, and the inhibition of IκBα phosphorylation and degradation, as well as the decrease of nuclear translocation of p65 in PC-3 cells.

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Abbreviations

ITC:

isothiocyanate

SFN:

sulforaphane

PEITC:

phenethyl isothiocyanate

NF-κB:

nuclear factor kappa B

IκBα:

inhibitor of NF-κB alpha

IKK:

IκB kinase

VEGF:

vascular endothelial growth factor

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Acknowledgements

We thank all the members of Dr Tony Kong's lab for their help in the preparation of this manuscript. Work described here was supported in part by institutional funds and Grant R01-CA073674 from the National Institutes of Health (NIH). We also acknowledge the support from NIH Grant R01-CA54999 to Dr Céline Gélinas.

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Changjiang Xu, Guoxiang Shen, Chi Chen & Ah-Ng Tony Kong

  2. Center for Advanced Biotechnology and Medicine, Piscataway, NJ, 08854, USA

    Céline Gélinas

  3. Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA

    Céline Gélinas

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  1. Changjiang Xu
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Correspondence to Ah-Ng Tony Kong.

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Xu, C., Shen, G., Chen, C. et al. Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24, 4486–4495 (2005). https://doi.org/10.1038/sj.onc.1208656

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