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Ether lipids inhibit the effects of phorbol diester tumor promoters

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Lipids

Abstract

Recent studies have shown that the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulates protein kinase C (PKC), whereas the ether-linked phospholipid 1-O-octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine (ET-18-OCH3) inhibits PKC activity in vitro. Therefore, the antitumor effects of ET-18-OCH3 could be due to its inhibition of PKC activity and the effects of tumor promotion. TPA stimulates arachidonic acid release, prostaglandin synthesis, phosphatidylcholine synthesis and the degradation of phosphatidylcholine by phospholipase C in Madin Darby canine kidney (MDCK) cells. Therefore, we have determined the effects of ET-18-OCH3 on these consequences of TPA stimulation. Preliminary experiments determined that ET-18-OCH3 inhibited PKC partially purified from MDCK cells by ion-exchange chromatography on DEAE-cellulose. In addition, ET-18-OCH3, inhibited the TPA-stimulated phosphorylation of a 40,000-dalton protein in intact MDCK cells. These data indicate that ET-18-OCH3 is an effective inhibitor of PKC activity in MDCK cells. In addition, ET-18-OCH3 was found to inhibit arachidonic acid release and prostaglandin synthesis. The inhibition of prostaglandin synthesis appears to be secondary to inhibition of arachidonic acid release, since ET-18-OCH3 does not inhibit TPA-stimulated synthesis of prostaglandin H synthase or the activity of the enzyme directly (Parker, J., Daniel, L. W., and Waite, M. [1987]J. Biol. Chem. 262, 5385–5393). ET-18-OCH3 also inhibits TPA-stimulated phosphatidylcholine synthesis and phosphatidylcholine degradation by phospholipase C. These data provide evidence that the antineoplastic ether lipids inhibit the biochemical effects of the tumor promoter TPA in intact cells and indicate that this inhibition may have a role in their biological activities.

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Abbreviations

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

PKC:

Ca2+-activated, phospholipid-dependent protein kinase

MDCK:

Madin Darby canine kidney

PC:

choline-containing phosphoglycerides

CI:

1-(5-isoquinolinsulfonyl)piperazine

CP 46,665:

4-aminomethyl-1-[2,3-(di-n-decycloxy)n-propyl]-4-phenylpiperidine dihydrochloride

ET-18-OCH3 :

1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

ET-18-H:

1-O-octadecylpropanediol-3-phosphocholine

ET-18-S-OCH3 :

1-S-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

TLC:

thin layer chromatography

PC-PLC:

a TPA-stimulated phospholipase C that degrades PC

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Authors and Affiliations

  1. Department of Biochemistry, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina

    Larry W. Daniel, Lori A. Etkin, Bennett T. Morrison & Judy Parker

  2. School of Pharmacy, Division of Medicanal Chemistry and Natural Products, University of North Carolina, Chapel Hill, North Carolina

    Susan Morris-Natschke, Jefferson R. Surles & Claude Plantadosi

Authors
  1. Larry W. Daniel
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  2. Lori A. Etkin
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  3. Bennett T. Morrison
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  4. Judy Parker
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  5. Susan Morris-Natschke
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  6. Jefferson R. Surles
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  7. Claude Plantadosi
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Daniel, L.W., Etkin, L.A., Morrison, B.T. et al. Ether lipids inhibit the effects of phorbol diester tumor promoters. Lipids 22, 851–855 (1987). https://doi.org/10.1007/BF02535543

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  • DOI: https://doi.org/10.1007/BF02535543

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