Inactivation of NF-κB by 3,3′-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells

Rahman, Khalilur; Ali, Shadan; Aboukameel, Amro; Sarkar, Sanila H.; Wang, Zhiwei; Philip, Philip A.; Sakr, Wael; Raz, Avraham

doi:10.1158/1535-7163.mct-07-0336

Cited by 100 publications

(92 citation statements)

References 49 publications

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“…Cyclin D1 and cMyc, two NF-B target genes have an important role in cell growth and proliferation (73,74), and key angiogenesis factors such as vascular endothelial growth factor (VEGF) and interleukin-8 (64), are directly or indirectly enhanced by NF-B activation. Cancer growth inhibition via NF-B inhibition has been shown in colon (75), and the similar results has been shown in other several flavors of human neoplasia such as lung (76) and breast (77). To investigate the role of NF-B in inflammation-induced tumor growth, one study of experimental murine colon cancer metastasis model revealed Volume 6 Number 5 October 2009 that lipopolysaccharide (LPS)-induced metastatic growth response depends on both TNF- production by host hematopoietic cells and NF-B activation in tumor cells.…”

Section: The Role Of Nf-b In Promoting Carcinogenesis Of Colorectalsupporting

confidence: 71%

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

et al. 2009

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There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B (NF-B), a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-B activation in inflammatory bowel diseases (

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Section: The Role Of Nf-b In Promoting Carcinogenesis Of Colorectalsupporting

confidence: 71%

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

et al. 2009

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“…LNCaP and C4-2B prostate cancer cells were seeded in 96-well plates. After 24 h, the cells were treated with 10, 30, and 40 Amol/L DIM followed by treatment of Taxotere with 0.5, 1.0, and 1.5 nmol/L for 24 to 72 h. After treatment, the cell growth studies were done by MTT as described earlier (26,27).…”

Section: Methodsmentioning

confidence: 99%

“…The cytoplasmic histone/DNA fragments from prostate cancer cells treated with 10 or 30 Amol/L DIM followed by treatment of Taxotere with 1.0 or 1.5 nmol/L for 24, 48, or 72 h were extracted and the Cell Death Detection ELISA Kit (Roche) was used to detect apoptosis in prostate cancer cells as described earlier (11,26,27).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that 3,3 ¶-diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of indole-3-carbinol, is thought to have protective effects against the development of human prostate cancer as well as breast cancer (11,(25)(26)(27)(28). DIM is known to act as a potent inducer of apoptosis associated with down-regulation of Akt/nuclear factornB (NF-nB) and survivin in breast cancer cells (11,26).…”

Section: Introductionmentioning

confidence: 99%

“…DIM is known to act as a potent inducer of apoptosis associated with down-regulation of Akt/nuclear factornB (NF-nB) and survivin in breast cancer cells (11,26). It has also been indicated that HRPC is an aggressive and treatmentresistant disease and the pharmacologic therapeutic approach for this disease has previously shown limited efficacy (29,30).…”

Section: Introductionmentioning

confidence: 99%

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3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation

et al. 2009

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Survivin, a member of inhibitor of apoptosis family, is associated with both prostate cancer progression and drug resistance. Therefore, we hypothesized that survivin may play a potentially important role in hormone-refractory prostate cancer (HRPC) and bone metastatic disease; thus, targeting of survivin signaling could enhance therapeutic efficacy in prostate cancer. 3,3 ¶-Diindolylmethane (DIM) has been known to have cancer chemoprevention activity. However, no information is available regarding the down-regulation of survivin by DIM, which could result in the chemosensitization of HRPC cells to Taxotere-induced killing. We investigated the effect of DIM alone or in combination with Taxotere using LNCaP and C4-2B prostate cancer cells. We observed that DIM enhanced Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in survivin expression as well as androgen receptor and nuclear factor-KB (NF-KB) DNA-binding activity. We also found that knockdown of survivin expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both prostate cancer cells. Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-KB-Luc activity in prostate cancer cells exposed to DIM and Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone tumor growth, and the results were correlated with the down-regulation of survivin. From these results, we conclude that inactivation of survivin by DIM enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of HRPC and metastatic prostate cancer. [Cancer Res 2009;69(10):4468-75]

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Oncogenic Ras mutant causes the hyperactivation of NF‐κB via acceleration of its transcriptional activation

et al. 2019

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It is well established that nuclear factor κB (NF‐κB) acts as one of the most important transcription factors for tumor initiation and progression, as it both protects cells from apoptotic/necrotic signals and accelerates angiogenesis and tumor metastasis, which is mediated via the expression of target genes. However, it has not yet been clarified how oncogenic signals accelerate the activation of NF‐κB. In the current study, we utilized untransformed NIH‐3T3 cells stably harboring a κB‐driven luciferase gene to show that an oncogenic mutant of Ras GTPase augmented TNFα‐induced NF‐κB activation. Notably, enforced expression of cyclin‐dependent kinase inhibitors, such as p27Kip1 and p21Cip1, effectively canceled the accelerated activation of NF‐κB, suggesting that oncogenic Ras‐induced cell cycle progression is essential for the hyperactivation of NF‐κB. Furthermore, we found that Ras (G12V) augmented the transcriptional activation of NF‐κB, and this activation required the p38 MAP kinase. We observed that a downstream kinase of p38 MAP kinase, MSK1, was activated by Ras (G12V) and catalyzed the phosphorylation of p65/RelA at Ser‐276, which is critical for its transcriptional activation. Significantly, phosphorylation of the p65/RelA subunit at Ser‐276 was elevated in patient samples of colorectal cancer harboring oncogenic mutations of the K‐Ras gene, and the expression levels of NF‐κB target genes were drastically enhanced in several cancer tissues. These observations strongly suggest that oncogenic signal‐induced acceleration of NF‐κB activation is caused by activation of the p38 MAP kinase–MSK1 signaling axis and by cell cycle progression in cancer cells.

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Inactivation of NF-κB by 3,3′-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells

Abstract: Constitutive activation of Akt or nuclear factor-KB

Cited by 100 publications

References 49 publications

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation

Oncogenic Ras mutant causes the hyperactivation of NF‐κB via acceleration of its transcriptional activation

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