Activation of NF-kappa B by antineoplastic agents - Role of protein kinase C

作者：Das KC; White CW

来源：Journal of Biological Chemistry, 1997, 272(23): 14914-14920.

DOI：10.1074/jbc.272.23.14914

Paclitaxel can induce tumor necrosis factor (TNF) and interleukin-1 gene expression, similar to lipopolysaccharides, Since lipopolysaccharide-induced expression of TNF is related to activation of NF-kappa B, we determined whether NP-kappa B could be activated by paclitaxel. In the human lung adenocarcinoma cell line A549, paclitaxel activated NF-kappa B in a dose-dependent manner with maximal activation after 2-4 h, Since paclitaxel could upregulate TNF and interleukin-1 secretion and subsequent NF-kappa B activation could be caused by these cytokines, the effect of two other groups of anticancer drugs including vinca alkaloids (vinblastine and vincristine) and anthracyclines (daunomycin and doxorubicin), neither of which induce TNF or interleukin-1 gene expression, were examined, Like paclitaxel, vinblastine, vincristine, daunomycin, and doxorubicin each caused activation of NF-kappa B. Therefore, it is unlikely that activation of NF-kappa B caused by these agents or by paclitaxel is mediated via cytokine up-regulation. Furthermore, actinomycin D and cycloheximide, inhibitors of transcription and translation, respectively, did not inhibit paclitaxel-induced NF-kappa B activation, Several other transcription factors such as AP-1, AP-2, CREB, SP-1, or TFIID were not activated by antineoplastic agents demonstrating specificity of NF-kappa B activation, The involvement of both subunits in the NF-kappa B DNA binding complex was demonstrated by its abrogation by anti-p65 and by supershift by anti-p50 antibodies. Since protein phosphorylation is implicated in the activation of NF-kappa B, the effect of anticancer drugs on protein kinase C activity was measured, Vincristine, daunomycin, and paclitaxel significantly increased protein kinase C activity, and vinblastine and doxorubicin caused similar trends, Following treatment with antineoplastics (1-4 h), cytoplasmic I kappa B alpha degradation occurred concomitantly with translocation of p65 to the nucleus, Specific protein kinase C inhibitors (bisindolylmaleimide (GF109203X) and calphostin C) blocked the activation of NF-kappa B by each compound. Hence, protein kinase C activation may contribute to NF-kappa B activation by antineoplastic agents.

• 出版日期1997-6-6