Kasperczyk, Hubert and La Ferla-Brühl, Katia and Westhoff, Mike Andrew and Behrend, Lars and Zwacka, Ralf Michael and Debatin, Klaus-Michael and Fulda, Simone (2005) Betulinic acid as new activator of NF-κB: molecular mechanisms and implications for cancer therapy. Oncogene, 24 (46). pp. 6945-6956. DOI https://doi.org/10.1038/sj.onc.1208842
Kasperczyk, Hubert and La Ferla-Brühl, Katia and Westhoff, Mike Andrew and Behrend, Lars and Zwacka, Ralf Michael and Debatin, Klaus-Michael and Fulda, Simone (2005) Betulinic acid as new activator of NF-κB: molecular mechanisms and implications for cancer therapy. Oncogene, 24 (46). pp. 6945-6956. DOI https://doi.org/10.1038/sj.onc.1208842
Kasperczyk, Hubert and La Ferla-Brühl, Katia and Westhoff, Mike Andrew and Behrend, Lars and Zwacka, Ralf Michael and Debatin, Klaus-Michael and Fulda, Simone (2005) Betulinic acid as new activator of NF-κB: molecular mechanisms and implications for cancer therapy. Oncogene, 24 (46). pp. 6945-6956. DOI https://doi.org/10.1038/sj.onc.1208842
Abstract
Recent evidence demonstrates that the anticancer activity of betulinic acid (BetA) can be markedly increased by combination protocols, for example with chemotherapy, ionizing radiation or TRAIL. Since nuclear factor-kappaB (NF-κB), a key regulator of stress-induced transcriptional activation, has been implicated in mediating apoptosis resistance, we investigated the role of NF-κB in BetA-induced apoptosis. Here, we provide for the first time evidence that BetA activates NF-κB in a variety of tumor cell lines. NF-κB DNA-binding complexes induced by BetA consisted of p50 and p65 subunits. Nuclear translocation of p65 was also confirmed by immunofluorescence microscopy. BetA-induced NF-κB activation involved increased IKK activity and phosphorylation of IκB-α at serine 32/36 followed by degradation of IκB-α. Reporter assays revealed that NF-κB activated by BetA is transcriptionally active. Interestingly, inhibition of BetA-induced NF-κB activation by different chemical inhibitors (proteasome inhibitor, antioxidant, IKK inhibitor) attenuated BetA-induced apoptosis. Importantly, specific NF-κB inhibition by transient or stable expression of IκB-α super-repressor inhibited BetA-induced apoptosis in SH-EP neuroblastoma cells, while transient expression of IκB-α super-repressor had no influence on BetA-induced apoptosis in two other cell lines. Thus, our findings that activation of NF-κB by BetA promotes BetA-induced apoptosis in a cell type-specific fashion indicate that NF-κB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols. © 2005 Nature Publishing Group. All rights reserved.
Item Type: | Article |
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Uncontrolled Keywords: | apoptosis; betulinic acid; cancer; NF-kappa B |
Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 29 Jun 2017 10:16 |
Last Modified: | 07 Aug 2024 20:07 |
URI: | http://repository.essex.ac.uk/id/eprint/8330 |