Paclitaxel-induced immune suppression is associated with NF-κB activation via conventional PKC isotypes in lipopolysaccharide-stimulated 70Z/3 pre-B-lymphocyte tumor cells

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Title
Paclitaxel-induced immune suppression is associated with NF-κB activation via conventional PKC isotypes in lipopolysaccharide-stimulated 70Z/3 pre-B-lymphocyte tumor cells
Author(s)
Michael Lee; Young Jin Jeon
Bibliographic Citation
Molecular Pharmacology, vol. 59, no. 2, pp. 248-253
Publication Year
2001
Abstract
Paclitaxel, a potent antitumor agent, has been shown to be lipopolysaccharide (LPS) mimetic in mice, stimulating signaling pathways and gene expression indistinguishably from LPS. In the present study, we showed the intracellular signaling pathway of paclitaxel-induced nuclear factor-κB (NF-κB) activation and its suppressive effect on LPS-induced signaling in murine 70Z/3 pre-B cells. Stimulation of 70Z/3 cells with LPS for 30 min caused activation of NF-κB in the nuclei by detection of DNA-protein binding specific to NF-κB. Similarly, paclitaxel also produced a marked and dose-related NF-κB activation. However, pretreatment of cells with 10/μM paclitaxel for 18 h resulted in complete inhibition of LPS-rnediated NF-κB activation. Interestingly, the activity of IκB kinase (IKK-β), which plays an essential role in NF-κB activation through IκB phosphorylation, was largely enhanced in paclitaxel-treated cells, detected as IκBα phosphorylation. Because protein kinase C (PKC) is implicated in the activation of NF-κB via IKK-β, the effect of paclitaxel on PKC activation was also measured. It was shown that NF-κB nuclear translocation and DNA binding in response to paclitaxel was completely blocked by the conventional PKC inhibitor, G? 6976. Moreover, immunoblotting analysis with paclitaxel-treated cell extract demonstrated that the conventional PKC isotype PKC-α was found to be involved in the regulation of paclitaxel-induced NF-κB activation, as determined by electrophoretic mobility shift of PKC. Therefore, these data suggest that paclitaxel may activate IKK-β via conventional PKC isotypes, resulting in NF-κB activation and, finally, desensitization of LPS-inducible signaling pathway in 70Z/3 pre-B cells.
ISSN
0026-895X
Publisher
Amer Soc Pharmacology Experimental Therapeutics
DOI
http://dx.doi.org/10.1124/mol.59.2.248
Type
Article
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1. Journal Articles > Journal Articles
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