Aberrant nuclear factor-κB activity and its participation in the growth of human malignant astrocytoma

Nagai, Shoichi; Washiyama, Kazuo; Kurimoto, Masanori; Takaku, Akira; Endo, Shunro; Kumanishi, Toshiro

doi:10.3171/jns.2002.96.5.0909

Cited by 103 publications

(86 citation statements)

References 25 publications

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“…It exhibits cytotoxic activity also against neuroectodermal (3,5,6) and brain tumor cells (4). Because NF-B is constitutively active in numerous tumors, including melanoma (59), and in brain tumors (60), and because NF-B activation has an antiapoptotic role, it is possible that the apoptotic effects of BA are mediated through the down-regulation of NF-B, as described in this study. Our results do indeed show that BA can potentiate the TNF-induced apoptosis mediated through the down-regulation of NF-B.…”

Section: Discussionmentioning

confidence: 95%

Betulinic Acid Suppresses Carcinogen-Induced NF-κB Activation Through Inhibition of IκBα Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9

Takada

Aggarwal

2003

The Journal of Immunology

206

152

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Betulinic acid (BA), a pentacyclic triterpene isolated from the bark of the white birch tree, has been reported to be a selective inducer of apoptosis in tumor cells. It also exhibits anti-inflammatory and immunomodulatory properties. How BA mediates these effects is not known. Because of the critical role of the transcription factor NF-κB in growth modulatory, inflammatory, and immune responses, we postulated that BA modulates the activity of this factor. In this study we investigated the effect of BA on NF-κB and NF-κB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. BA suppressed NF-κB activation induced by TNF, PMA, cigarette smoke, okadaic acid, IL-1, and H2O2. The suppression of NF-κB activation was not cell-type specific. BA suppressed the activation of IκBα kinase, thus abrogating the phosphorylation and degradation of IκBα. We found that BA inhibited NF-κB activated by TNFR 1, TNFR-associated death domain, TNFR-associated factor 2, NF-κB-inducing kinase, and IκBα kinase. Treatment of cells with this triterpinoid also suppressed NF-κB-dependent reporter gene expression and the production of NF-κB-regulated gene products such as cyclooxygenase-2 and matrix metaloproteinase-9 induced by inflammatory stimuli. Furthermore, BA enhanced TNF-induced apoptosis. Overall, our results indicated that BA inhibits activation of NF-κB and NF-κB-regulated gene expression induced by carcinogens and inflammatory stimuli. This may provide a molecular basis for the ability of BA to mediate apoptosis, suppress inflammation, and modulate the immune response.

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Section: Discussionmentioning

confidence: 95%

Betulinic Acid Suppresses Carcinogen-Induced NF-κB Activation Through Inhibition of IκBα Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9

Takada

Aggarwal

2003

The Journal of Immunology

206

152

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“…Rac1 is activated by hypoxia and required for HIF-1a expression and transcriptional activity (Hirota and Semenza, 2001), a condition commonly found in GBM. In addition, human malignant astrocytoma cells and high-grade astrocytoma tissue show aberrant NF-kB activity, which promotes their growth (Nagai et al, 2002). Therefore, one is tempted to speculate that inactivation of IL-6 in our v-src þ /À /IL-6 À/À mice foiled the establishment of an autocrine IL-6 activation loop leading to impaired tumour formation.…”

Section: Discussionmentioning

confidence: 97%

IL-6 is required for glioma development in a mouse model

et al. 2004

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The pleiotropic cytokine interleukin-6 (IL-6) contributes to malignant progression and apoptosis resistance of various cancer types. Although IL-6 is elevated in malignant gliomas, and glioma cells respond to IL-6, its functional role in gliomagenesis is unclear. We have investigated this role of IL-6 in a mouse model of spontaneous astrocytoma by crossbreeding glial fibrillary acidic protein (GFAP)-viral src oncogene transgenic mice with IL-6-deficient mice. We show here that ablation of IL-6 prevents tumour formation in these predisposed animals, but did not affect preneoplastic astrogliosis. Moreover, we demonstrate phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT)3, a prerequisite for IL-6 signalling, in 51 human gliomas WHO grade II-IV and all experimental mouse tumours investigated. Together with the observation that STAT3 activation increases with malignancy, these findings indicate an important role for IL-6 in the development and malignant progression of astrocytomas.

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“…One common feature of most GBM is a hyperactive NF-kB pathway (Hayashi et al, 2001), and the rate of growth of these cells paralleled the activity of this pathway in these tumors (Nagai et al, 2002). Therefore, this pathway becomes an important therapeutic target for these tumors.…”

Section: Discussionmentioning

confidence: 99%

Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)

et al. 2004

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The proteasome plays a pivotal role in controlling cell proliferation, apoptosis, and differentiation in a variety of normal and tumor cells. PS-341, a novel boronic acid dipeptide that inhibits 26S proteasome activity, has prominent effects in vitro and in vivo against several solid tumors. We examined its antiproliferation, proapoptotic effects using three human glioblastoma multiforme (GBM) cell lines and five primary GBM explants. PS-341 markedly inhibited proliferation of GBM cell lines and explants in liquid and soft agar culture. These cells developed a G2/M cell cycle arrest with a concomitant decreased percentage of cells in S phase (E2-fold), associated with an increased expression of p21 WAF1 , p27 KIP1 , as well as cyclin B1 and decreased levels of CDK2, CDK4, and E2F4. About 35-40% of the cells became apoptotic when exposed to PS-341 (10 À7 M, 24-48 h) as shown by Annexin V analysis; in concert with these findings, immunobloting showed a C-terminal 85 kDa apoptotic fragment of poly ADP-ribose polymerase (PARP), and a decreased level of Bcl2 and Bcl-xl. PS-341 downregulated the expression of Bcl-2 and Bcl-xl in protein levels at an early time of treatment. These changes occurred irrespective of the p53 mutational status of the cells. PS-341 activated JNK/c-Jun signaling in GBM cells, and the JNK inhibitor SP600125 blocked the JNK signaling to reverse partially the PS-341 growth inhibition. PS-341 (10 À7 M, 24 h) decreased nuclear NF-jB levels as shown by Western blot, and reduced transcriptional activity of NF-jB as measured by reporter assays in these transformed cells. Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing ligand) and TNFa (tumor necrosis factor alpha) induced cell death and apoptosis (two-to five-fold) in GBM cells. In summary, PS-341 has profound effects on growth and apoptosis of GBM cells, suggesting that PS-341 may be an effective therapy for patients with gliomas.

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Aberrant nuclear factor-κB activity and its participation in the growth of human malignant astrocytoma

Cited by 103 publications

References 25 publications

Betulinic Acid Suppresses Carcinogen-Induced NF-κB Activation Through Inhibition of IκBα Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9

Betulinic Acid Suppresses Carcinogen-Induced NF-κB Activation Through Inhibition of IκBα Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9

IL-6 is required for glioma development in a mouse model

Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)

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