Indole-3-carbinol-induced modulation of NF-κB signalling is breast cancer cell-specific and does not correlate with cell death

Moiseeva, Elena P.; Heukers, Raimond

doi:10.1007/s10549-007-9669-6

Cited by 9 publications

(6 citation statements)

References 68 publications

(2 reference statements)

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“…Interestingly, siRNA knockdown of PTEN expression, a phosphatase known to reduce AKT activity in cancer cells (36), did not prevent I3C downregulation of total NF-κB activity. Thus, in contrast to observations in other cell systems (8,37), our results in human breast cancer cells directly show that the PTEN/Akt signaling cascade is not involved in I3C-mediated downregulation of NF-κB transcriptional activity.…”

Section: I3c Disrupts the Elastase-dependent Stimulation Of Nf-κb Tracontrasting

confidence: 99%

“…Previous studies correlated the inactivation of NF-κB with treatment by I3C and related indoles (8,43); however, the precise cellular mechanism remained elusive because the direct indole target protein was unknown. By extending our studies demonstrating that I3C is a noncompetitive inhibitor of elastase enzymatic activity (16), we have uncovered a novel indole-regulated cellular cascade in which the I3C-elastase interaction modulates the protein processing and signaling of CD40, a member of TNF receptor superfamily, which then triggers the disruption in NF-κB nuclear localization resulting in the downregulation of NF-κB transcription factor activity and altered expression of its target genes.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have established that I3C treatment of human reproductive cancer cells modulates specific transcriptional, signal transduction, and metabolic cascades that lead to a cell cycle arrest, apoptosis, downregulation of migration, and regulation of hormone receptor signaling (3,4,7). Key downstream targets of I3C signaling that are consistently observed in different human cancer cell types include transcription factors such as Sp1 and NF-κB and their target genes (7,8); the p53 tumor suppressor protein (9); specific cell cycle components such as the G 1 acting CDKs, CDK inhibitors, cyclin E, and cyclin D (10,11); signal transduction components such as Akt, RhoA kinase (12), and protein kinases, estrogen and androgen receptors (13); and various apoptosis-related genes (14,15).…”

Section: Introductionmentioning

confidence: 99%

“…Previous investigations have correlated the loss of NF-κB transcriptional signaling with indole-mediated antiproliferative pathways (8); however, the precise mechanism of NF-κB inactivation by indoles remains elusive. In this study, we have established for the first time that the I3C inhibition of extracellular elastase cleavage of plasma membrane CD40 modulates signaling through its associated TRAF molecules and thereby leads to NF-κB inactivation.…”

Section: Introductionmentioning

confidence: 99%

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Direct Inhibition of Elastase Activity by Indole-3-Carbinol Triggers a CD40-TRAF Regulatory Cascade That Disrupts NF-κB Transcriptional Activity in Human Breast Cancer Cells

2010

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Treatment of highly tumorigenic MDA-MB-231 human breast cancer cells with indole-3-carbinol (I3C) directly inhibited the extracellular elastase-dependent cleavage of membrane-associated CD40, a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 signaling has been implicated in regulating cell survival, apoptosis, and proliferation, as well as in sensitizing breast cancer cells to chemotherapy, and is therefore an important potential target of novel breast cancer treatments. The I3C-dependent accumulation of full-length unprocessed CD40 protein caused a shift in CD40 signaling through TNF receptor-associated factors (TRAF), including the TRAF1/TRAF2 positive regulators and TRAF3 negative regulator of NF-kappaB transcription factor activity. Because TRAF1 is a transcriptional target gene of NF-kappaB, I3C disrupted a positive feedback loop involving these critical cell survival components. siRNA ablation of elastase expression mimicked the I3C inhibition of CD40 protein processing and G(1) cell cycle arrest, whereas siRNA knockdown of TRAF3 and the NF-kappaB inhibitor IkappaB prevented the I3C-induced cell cycle arrest. In contrast, siRNA knockdown of PTEN had no effect on the I3C control of NF-kappaB activity, showing the importance of CD40 signaling in regulating this transcription factor. Our study provides the first direct in vitro evidence that I3C directly inhibits the elastase-mediated proteolytic processing of CD40, which alters downstream signaling to disrupt NF-kappaB-induced cell survival and proliferative responses. Furthermore, we have established a new I3C-mediated antiproliferative cascade that has significant therapeutic potential for treatment of human cancers associated with high levels of elastase and its CD40 membrane substrate.

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Section: I3c Disrupts the Elastase-dependent Stimulation Of Nf-κb Tracontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Direct Inhibition of Elastase Activity by Indole-3-Carbinol Triggers a CD40-TRAF Regulatory Cascade That Disrupts NF-κB Transcriptional Activity in Human Breast Cancer Cells

2010

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“…Down stream targets of I3C signaling include transcription factors such as Sp1 and NFκB and their target genes [28, 29], the p53 tumor suppressor protein [12], and specific cell cycle components such as the G1 acting CDKs, CDK inhibitors, cyclin E and cyclin D [11, 13, 14, 28, 30]. In human breast cancer cells, a response specific to the I3C cell cycle arrest is the disruption of Sp1 interactions with the CDK6 promoter, which accounts for the loss of CDK6 promoter activity and gene expression [28].…”

Section: Introductionmentioning

confidence: 99%

1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells

Nguyen

Лавренов

Sundar

et al. 2010

Chemico-Biological Interactions

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Indole-3-carbinol (I3C), a natural autolysis product of a gluccosinolate present in Brassica vegetables such as broccoli and cabbage, has anti-proliferative and anti-estrogenic activities in human breast cancer cells. A new and significantly more potent I3C analogue, 1-benzyl-I3C was synthesized, and in comparison to I3C, this novel derivative displayed an approximate 1000-fold enhanced potency in suppressing the growth of both estrogen responsive (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cells (I3C IC50 of 52 μM, and 1-benzyl-I3C IC50 of 0.05 μM). At significantly lower concentrations, 1-benzyl-I3C induced a robust G1 cell cycle arrest and elicited the key I3C-specific effects on expression and activity of G1 acting cell cycle genes including the disruption of endogenous interactions of the Sp1 transcription factor with the CDK6 promoter. Furthermore, in estrogen responsive MCF-7 cells, with enhanced potency 1-benzyl-I3C down regulated production of estrogen receptor-alpha protein, acts with tamoxifen to arrest breast cancer cell growth more effectively than either compound alone, and inhibited the in vivo growth of human breast cancer cell-derived tumor xenografts in athymic mice. Our results implicate 1-benzyl-I3C as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of indole-sensitive cancers.

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Cancer Chemopreventive Activity of Higher Plants

Kinghorn¹,

Ren²,

Li³

et al. 2012

Plant Bioactives and Drug Discovery

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Indole-3-carbinol-induced modulation of NF-κB signalling is breast cancer cell-specific and does not correlate with cell death

Cited by 9 publications

References 68 publications

Direct Inhibition of Elastase Activity by Indole-3-Carbinol Triggers a CD40-TRAF Regulatory Cascade That Disrupts NF-κB Transcriptional Activity in Human Breast Cancer Cells

Direct Inhibition of Elastase Activity by Indole-3-Carbinol Triggers a CD40-TRAF Regulatory Cascade That Disrupts NF-κB Transcriptional Activity in Human Breast Cancer Cells

1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells

Cancer Chemopreventive Activity of Higher Plants

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