Protein kinase Cdelta-dependent induction of manganese superoxide dismutase gene expression by microtubule-active anticancer drugs.
Bacterial lipopolysaccharide can induce manganese superoxide dismutase (MnSOD) gene expression in a variety of cells. Paclitaxel (taxol) shares many properties of lipopolysaccharide. Here we report that paclitaxel can induce MnSOD gene expression in human lung adenocarcinoma cell line A549 in a time- and dose-dependent manner. Additional anticancer drugs, vinblastine and vincristine, also induced MnSOD gene expression. We have shown previously (Das, K. C., and White, C. W. (1997) J. Biol. Chem. 272, 14914-14920) that these drugs can activate protein kinase C (PKC). The PKC agonists thymeleatoxin (0.5 microM) and 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA; 10 nM) potently induced MnSOD gene expression. Calphostin C and GF109203X, both specific inhibitors of PKC, each inhibited MnSOD gene expression by anticancer agents. Down-regulation of PKC by prolonged treatment with phorbol 12-myristate 13-acetate (PMA) also inhibited induction of MnSOD by anticancer drugs, indicating an important role of PKC in MnSOD signaling by these agents. Of 11 PKC isoenzymes, only PKCdelta translocated to the cell membrane after stimulation with anticancer drugs. By contrast, dPPA, PMA, and thymeleatoxin caused translocation of PKCalpha, betaI, delta, and mu isotypes. Anticancer drug-stimulated cells also had increased total PKC activity in membrane and cytosolic fractions. Thus, paclitaxel, vinblastine, and vincristine each specifically activate PKCdelta, whereas PMA, thymeleatoxin, and dPPA activate multiple isoenzymes. PKCdelta was the only isoform activated by each agent in both groups of compounds effective in MnSOD induction.
Das
K C
KC
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. kumunda@uthct.edu
Guo
X L
XL
White
C W
CW
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D009281:Naphthalenes; D010703:Phorbol Esters; D012333:RNA, Messenger; D011994:Recombinant Proteins; C029705:12-deoxyphorbolphenylacetate-20-acetate; D014750:Vincristine; D014747:Vinblastine; C080287:thymeleatoxin; D013482:Superoxide Dismutase; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C058819:calphostin C; C070515:bisindolylmaleimide I; D017239:Paclitaxel