title: Activation of NF-kappaB by antineoplastic agents. Role of protein kinase C.
abstract: 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-kappaB, we determined whether NF-kappaB could be activated by paclitaxel. In the human lung adenocarcinoma cell line A549, paclitaxel activated NF-kappaB in a dose-dependent manner with maximal activation after 2-4 h. Since paclitaxel could up-regulate TNF and interleukin-1 secretion and subsequent NF-kappaB 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-kappaB. Therefore, it is unlikely that activation of NF-kappaB 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-kappaB 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-kappaB activation. The involvement of both subunits in the NF-kappaB 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-kappaB, 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 IkappaBalpha 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-kappaB by each compound. Hence, protein kinase C activation may contribute to NF-kappaB activation by antineoplastic agents.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Das
authors.forename: C W
authors.initials: CW
authors.lastname: White
mesh_terms: D000230:Adenocarcinoma; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D003609:Dactinomycin; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003513:Cycloheximide; D011493:Protein Kinase C; D017239:Paclitaxel; D003630:Daunorubicin