Tumor-Promoting Phorbol Diesters are Substrates for and Modulators of Diacylglycerol Lipase

  • Myles C. Cabot
  • Holly Chabbott
  • Zu-chuan Zhang
Part of the NATO ASI Series book series (NSSA, volume 116)

Abstract

12-0-Tetradecanoylphorbol-13-acetate (TPA) promotes epidermal carcinogenesis in micel and can induce or inhibit cellular differentiation in vitro 2. The biological activity of the phorbol esters is due, in part, to the ability of these agents to mimic the action of diacylglycerols in the protein kinase C activation cascade3,4. Because phorbol diesters elicit a variety of responses when added to cell cultures5, their metabolism, compared with the natural diacylglycerol mediators, was investigated. It was of interest to assess what type of enzyme degrades TPA, as several studies have shown phorbol diester hydrolase in serum and cell preparations (see ref. 6 for brief review) with little information on the substrate specificity. Our studies show that diacylglycerols and TPA are hydrolyzed by rat serum enzymes that are sensitive to RHC 802677, a diacylglycerol lipase inhibitor8. These data complement the idea that agents like TPA mimic diacylglycerols. Further, we have synthesized several diacylglycerols that are structurally analogous to the long chain-short chain diradyl grouping of TPA. These lipids are highly reactive lipase substrates9 whose hydrolysis is inhibited by the presence of phorbol diesters in the incubation mixture. These results show that phorbol diesters resemble diacylglycerols closely enough to not only serve as substrates for lipolytic enzymes but additionally to modulate lipase activity.

Keywords

Cholesterol Hydrolysis Glycerol Acetone Chloroform 

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Myles C. Cabot
    • 1
  • Holly Chabbott
    • 1
  • Zu-chuan Zhang
    • 2
  1. 1.W. Alton Jones Cell Science Center, Inc.Lake PlacidUSA
  2. 2.Shanghai Institute of BiochemistryShanghaiChina

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