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

Changjiang Xu; Guoxiang Shen; Chi Chen; Céline Gélinas; Ah Ng Tony Kong

doi:10.1038/sj.onc.1208656

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

Changjiang Xu, Guoxiang Shen, Chi Chen, Céline Gélinas, Ah Ng Tony Kong

Food Science and Nutrition

Research output: Contribution to journal › Article › peer-review

286 Scopus citations

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 μM) and PEITC (5 and 7.5 μM) significantly inhibited NF-κB transcriptional activity, nuclear transloction of p65, and gene expression of NF-κB-regulated VEGF, cylcin D1, and Bcl-X_L 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-X_L 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-X_L 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-X_L 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.

Original language	English (US)
Pages (from-to)	4486-4495
Number of pages	10
Journal	Oncogene
Volume	24
Issue number	28
DOIs	https://doi.org/10.1038/sj.onc.1208656
State	Published - Jun 30 2005

Bibliographical note

Funding Information:
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.

Keywords

IKK
IκBα
NF-κB
Phenethyl isothiocyanate
Sulforaphane

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.onc.1208656

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title = "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",

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 μM) and PEITC (5 and 7.5 μM) 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.",

keywords = "IKK, IκBα, NF-κB, Phenethyl isothiocyanate, Sulforaphane",

author = "Changjiang Xu and Guoxiang Shen and Chi Chen and C{\'e}line G{\'e}linas and Kong, {Ah Ng Tony}",

note = "Funding Information: We thank all the members of Dr Tony Kong{\textquoteright}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 C{\'e}line G{\'e}linas.",

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doi = "10.1038/sj.onc.1208656",

language = "English (US)",

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pages = "4486--4495",

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T1 - 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

AU - Xu, Changjiang

AU - Shen, Guoxiang

AU - Chen, Chi

AU - Gélinas, Céline

AU - Kong, Ah Ng Tony

N1 - Funding Information: 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.

PY - 2005/6/30

Y1 - 2005/6/30

N2 - 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 μM) and PEITC (5 and 7.5 μM) 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.

AB - 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 μM) and PEITC (5 and 7.5 μM) 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.

KW - IKK

KW - IκBα

KW - NF-κB

KW - Phenethyl isothiocyanate

KW - Sulforaphane

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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

Abstract

Bibliographical note

Keywords

UN SDGs

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