Betulinic acid as new activator of NF-κB: molecular mechanisms and implications for cancer therapy

Kasperczyk, Hubert; Ferla-Brühl, Katia La; Westhoff, Mike‐Andrew; Behrend, Lars; Zwacka, Ralf M.; Debatin, Klaus‐Michael; Fulda, Simone

doi:10.1038/sj.onc.1208842

Cited by 139 publications

(106 citation statements)

References 30 publications

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“…Accordingly, topoisomerase II inhibitors that intercalate into the DNA such as doxorubicin, daunorubicin, and mitoxantrone trigger NF-kB activation before the induction of apoptosis, and NF-kB inhibition significantly reduces apoptosis (24). In addition, a proapoptotic function of NF-kB has been described in several systems of neuronal cell death, for example, induced by ischemia, glutamate, betulinic acid, or NMDA receptors stimulation (25,(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear extracts were prepared as previously described (25). In brief, cells were washed, scraped, and collected by centrifugation at 1,000 Â g for 5 minutes at 4 C. Cells were resuspended in low salt buffer, allowed to swell on ice for 12 minutes, followed by addition of a 10% Igepal CA-630 solution and centrifugation.…”

Section: Nuclear Protein Extraction and Electrophoretic Mobility Shifmentioning

confidence: 99%

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NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Berger

Jennewein²,

Marschall³

et al. 2011

Molecular Cancer Therapeutics

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Evasion of apoptosis contributes to radioresistance of glioblastoma, calling for novel strategies to overcome apoptosis resistance. In this study, we investigated the potential of the small molecule Smac mimetic BV6 to modulate radiosensitivity of glioblastoma cells. Here, we identify a novel proapoptotic function of NF-kB in g-irradiation-induced apoptosis of glioblastoma cells by showing, for the first time, that NF-kB is critically required for Smac mimetic-mediated radiosensitization. BV6 significantly increases g-irradiation-triggered apoptosis in several glioblastoma cell lines in a dose-and time-dependent manner. Calculation of combination index (CI) reveals that the interaction of BV6 and g-irradiation is highly synergistic (CI < 0.3). Molecular studies show that BV6 stimulates NF-kB activation, which is critical for radiosensitization, because genetic inhibition of NF-kB by overexpression of the dominant-negative superrepressor IkBa-SR significantly decreases BV6-and g-irradiation-induced apoptosis. Also, the BV6-mediated enhancement of g-irradiation-triggered caspase activation, drop of mitochondrial membrane potential, and cytochrome c release is abolished in cells overexpressing IkBa-SR. Similarly, NF-kB inhibition by ectopic expression of a kinase dead mutant of IKKb prevents the BV6-mediated sensitization for g-irradiation. The clinical relevance is underscored by experiments with primary tumor samples showing that BV6 sensitizes primary cultured glioma cells as well as glioblastoma-initiating cancer stem cells derived from surgical specimens for g-irradiation. In conclusion, we identify NF-kB as a critical mediator of Smac mimetic-conferred radiosensitization of glioblastoma cells. These results have important implications for the development of Smac mimetic-based combination protocols for radiosensitization of glioblastoma. Mol Cancer Ther; 10(10); 1867-75. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Nuclear Protein Extraction and Electrophoretic Mobility Shifmentioning

confidence: 99%

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Berger

Jennewein²,

Marschall³

et al. 2011

Molecular Cancer Therapeutics

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“…99). The InB-SR protein contains serine-to-alanine changes at amino acid residues 32 and 36, preventing phosphorylation and subsequent degradation by ubiquination of the InB protein and consequently NF-nB activation (60).…”

Section: Adenoviral Constructs and Adenoviral Transductionmentioning

confidence: 99%

“…To control for effects of adenoviral transduction and RNAi, a control vector containing a motif against EGFP was used (Ad.shRNA.EGFP). Adenoviral vectors were produced as described before (99,100,101). Adenoviral vector transductions were carried out in medium containing 2% FCS and 1% penicillin/streptomycin overnight, 24 hours after plating of the cells.…”

Section: Adenoviral Constructs and Adenoviral Transductionmentioning

confidence: 99%

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Braeuer

Büneker

Mohr

et al. 2006

Molecular Cancer Research

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The tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-KB (NF-KB) has been implicated, but its exact role is controversial. We studied different cell lines displaying varying responses to TRAIL and found that TRAIL can activate NF-KB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-KB via adenoviral expression of the IKB-A super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-KB, pointing to a possible role of preactivated NF-KB in protection from TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-KB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-KB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-KB and/or XIAP only in tumor cells with constitutively

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“…18 All chemicals were obtained from Sigma (Steinheim, Germany) unless otherwise indicated. TNFa was purchased from Biochrom (Berlin, Germany), TRAIL from R&D Systems (Wiesbaden, Germany), benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD.fmk) from Bachem (Bubendorf, Switzerland), BMS-345541 from Calbiochem (Darmstadt, Germany) and doxorubicin, VP16, cisplatin and taxol from Sigma.…”

Section: Cell Culture and Materialsmentioning

confidence: 99%

Sensitization of neuroblastoma cells for TRAIL‐induced apoptosis by NF‐κB inhibition

Ammann

Haag

Kasperczyk

et al. 2008

Intl Journal of Cancer

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The transcription factor nuclear factor‐kappaB (NF‐κB) plays a central role in stress‐induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF‐κB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF‐κB activation, whereas cisplatin and taxol have no impact on NF‐κB activity. Specific inhibition of NF‐κB activation by overexpression of dominant‐negative mutant IκBα‐super‐repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin‐ or VP16‐mediated NF‐κB activation. By comparison, inhibition of TRAIL‐stimulated NF‐κB activation by IκBα‐superrepressor or the small molecule NF‐κB inhibitor BMS‐345541 significantly enhances TRAIL‐induced apoptosis, pointing to an antiapoptotic function of NF‐κB in TRAIL‐mediated apoptosis. Analysis of signaling pathways reveals that NF‐κB inhibition prevents TRAIL‐triggered up‐regulation of Mcl‐1, promoting TRAIL‐induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl‐1 by RNA interference significantly enhances TRAIL‐induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95‐ or chemotherapy‐induced apoptosis. In conclusion, NF‐κB regulates apoptosis in a stimulus‐specific manner in neuroblastoma cells and confers protection against TRAIL‐induced apoptosis. By demonstrating that NF‐κB inhibition sensitizes neuroblastoma cells for TRAIL‐induced apoptosis, our findings have important implications. Thus, NF‐κB inhibitors may open new perspectives to potentiate the efficacy of TRAIL‐based protocols in the treatment of neuroblastoma. © 2008 Wiley‐Liss, Inc.

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Betulinic acid as new activator of NF-κB: molecular mechanisms and implications for cancer therapy

Cited by 139 publications

References 30 publications

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Sensitization of neuroblastoma cells for TRAIL‐induced apoptosis by NF‐κB inhibition

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