Autocrine regulation of TPA-induced apoptosis in monoblastic cell-line U-937: role for TNF-alpha, MnSOD and IL-6.
The present studies were undertaken to analyse the factors regulating TPA-induced apoptosis. Treatment of the monoblastic U-937 cells with the phorbol ester, TPA, was found to induce apoptosis in two distinct phases. In phase I (from 0 to 72 hours following TPA induction), apoptotic cells appeared, despite the expression of high levels of the anti-apoptotic Bcl-2 protein. After 96 h. of TPA treatment (phase II), the percentage of apoptotic cells increased as did the cell differentiation stage. The first phase apoptotic response could be significantly reduced (70%) by treatment with anti-tumor necrosis factor-alpha (TNF-alpha) antibody. TNF-alpha protein required de novo RNA and protein synthesis and was found to be mediated by protein kinase and protein tyrosine kinases. Manganese superoxide dismutase (MnSOD) inhibited, whereas IL-6 increased TPA-induced apoptosis. These findings suggest that both TPA, via TNF-alpha synthesis, exerts its protective function intracellularly by inducing MnSOD production and IL-6 may be an effective adjunct to TNF-alpha in the clinic, increasing the antitumor potency of this cytokine.
Champelovier
P
P
Département de Biologie et de Pathologie de la Cellule, Centre Hospitalier Universitaire de Grenoble, Hôpital Albert Michallon, France. Pierre.Champelovier@ujf-grenoble.fr
Richard
M J
MJ
Seigneurin
D
D
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication; D003994:Bucladesine / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D008345:Manganese / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D020298:U937 Cells / Q000187:drug effects* / Q000378:metabolism
D002087:Butyrates; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D007378:Interleukins; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D008345:Manganese; D003994:Bucladesine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003513:Cycloheximide; D019833:Genistein; D000242:Cyclic AMP; D013482:Superoxide Dismutase; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine