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ET-18-OCH3 inhibits nuclear factor-kappa B activation by 12-O-tetradecanoylphorbol-13-acetate but not by tumor necrosis factor-alpha or interleukin 1 alpha.

Abstract
1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) is a synthetic diether phospholipid that is competitive with phosphatidylserine binding to the regulatory domain of protein kinase C (PKC). Our previous studies indicate that the selective inhibition of tumor cell growth by ET-18-OCH3 may be due to altered signal transduction mechanisms, including the inhibition of PKC. To further define the mechanism of action of ET-18-OCH3, we have used it to study the role of PKC in regulation of the transcription factor NF-kappa B, which is activated by diverse stimuli. In the 293.27.2 human kidney cell line, as in hematopoietic cells of all lineages, NF-kappa B is stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha). The response to either TNF-alpha or IL-1 alpha is synergistically enhanced by TPA. However, the regulatory mechanisms and signal transduction systems responsible for NF-kappa B activation in response to these different stimuli have not been determined in detail. We have used ET-18-OCH3 and auranofin, which inhibit PKC by different mechanisms, to assess the role of PKC in NF-kappa B activation. ET-18-OCH3 markedly inhibits TPA-induced NF-kappa B activation, as measured by HIV long terminal repeat-directed expression of beta-galactosidase. The IC50 for inhibition by ET-18-OCH3 is approximately 2 microM, a noncytotoxic concentration. Inhibition of TPA-induced NF-kappa B activation was dependent upon preincubation with ET-18-OCH3, and the drug was active at approximately 2 mol% of total cellular phospholipid. ET-18-OCH3 did not inhibit NF-kappa B activation by either TNF-alpha or IL-1 alpha, indicating that there are multiple distinct signal transduction pathways leading to activation of NF-kappa B. We have confirmed these results using auranofin, an antirheumatic drug that is a specific PKC inhibitor interacting with the catalytic domain. Like ET-18-OCH3, auranofin blocked NF-kappa B activation by TPA but not by TNF-alpha or IL-1 alpha. Also like the ether lipid, auranofin only partially blocked the synergy exhibited by TPA and TNF-alpha. To confirm the role of NF-kappa B in this response, we measured NF-kappa B by electrophoretic mobility shift assay. Both ET-18-OCH3 and auranofin inhibited cellular induction of the active NF-kappa B complex in response to TPA but not in response to TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
AuthorsL W Daniel, F Civoli, M A Rogers, P K Smitherman, P A Raju, M Roederer
JournalCancer research (Cancer Res) Vol. 55 Issue 21 Pg. 4844-9 (Nov 1 1995) ISSN: 0008-5472 [Print] UNITED STATES
PMID7585518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Carcinogens
  • Enzyme Inhibitors
  • Interleukin-1
  • NF-kappa B
  • Phospholipid Ethers
  • Tumor Necrosis Factor-alpha
  • edelfosine
  • Auranofin
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
Topics
  • Antineoplastic Agents (pharmacology)
  • Auranofin (pharmacology)
  • Carcinogens (antagonists & inhibitors, pharmacology)
  • Cell Line
  • Cell Survival (drug effects)
  • Drug Interactions
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression (drug effects)
  • HIV (genetics)
  • Humans
  • Interleukin-1 (pharmacology)
  • Kidney (cytology)
  • NF-kappa B (antagonists & inhibitors, drug effects)
  • Phospholipid Ethers (pharmacology)
  • Protein Kinase C (antagonists & inhibitors, physiology)
  • Repetitive Sequences, Nucleic Acid
  • Stimulation, Chemical
  • Tetradecanoylphorbol Acetate (antagonists & inhibitors, pharmacology)
  • Transfection
  • Tumor Necrosis Factor-alpha (pharmacology)

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