Ether lipids inhibit the effects of phorbol diester tumor promoters.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Daniel
L W
LW
Department of Biochemistry, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27103.
Etkin
L A
LA
Morrison
B T
BT
Parker
J
J
Morris-Natschke
S
S
Surles
J R
JR
Piantadosi
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D005994:Glycerophosphates / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D002273:Carcinogens; D005994:Glycerophosphates; D010742:Phospholipid Ethers; C026659:edelfosine; D013755:Tetradecanoylphorbol Acetate