TY - JOUR
T1 - Paclitaxel-induced immune suppression is associated with NF-κB activation via conventional PKC isotypes in lipopolysaccharide-stimulated 70Z/3 pre-B lymphocyte tumor cells
AU - Lee, Michael
AU - Jeon, Young Jin
PY - 2001
Y1 - 2001
N2 - 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, Gö 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.
AB - 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, Gö 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.
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U2 - 10.1124/mol.59.2.248
DO - 10.1124/mol.59.2.248
M3 - Article
C2 - 11160860
AN - SCOPUS:0035139058
SN - 0026-895X
VL - 59
SP - 248
EP - 253
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -