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

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. ISSN 0950-9232

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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
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: Elements
Depositing User: Elements
Date Deposited: 29 Jun 2017 10:16
Last Modified: 18 Aug 2022 11:33

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