A metabolite of an antineoplastic ether phospholipid may inhibit transmembrane signalling via protein kinase C.

Lipids ·Vol. 22 ·No. 11 ·1987-11-00 ·Pages 842-6

van Blitterswijk WJ, van der Bend RL, Kramer IM, Verhoeven AJ, Hilkmann H, de Widt J

Abstract

In our search for the mechanisms by which the drug 1-O-alkyl-2-O-methylglycero-3-phosphocholine (AMG-PC) inhibits tumor growth and metastasis, we have detected a metabolite, 1-O-alkyl-2-O-methylglycerol (AMG), in membranes of MO4 mouse fibrosarcoma cells grown in the presence of the drug. Synthetic AMG inhibited the activation of highly purified human protein kinase C by diacylglycerol in the presence of phosphatidylserine. Furthermore, AMG also inhibited the receptor-specific binding of 3H-phorbol-12,13-dibutyrate to human HL-60 promyeloid leukemia cells in a dose-dependent fashion. AMG-PC was not effective or much less so in these assays. We suggest that interaction of the metabolite AMG with protein kinase C may inhibit stimulus-response coupling in tumor cells and may thus potentially contribute to the mechanism by which AMG-PC exerts its anticancer activities.

MeSH Terms

Animals Antineoplastic Agents/pharmacology Cell Line Fibrosarcoma Glyceryl Ethers/pharmacology Mice Mice, Inbred C3H Neoplasm Invasiveness Phorbol Esters/metabolism Phospholipid Ethers/pharmacology Protein Kinase C/metabolism Tumor Cells, Cultured/drug effects,enzymology

Chemicals

Antineoplastic Agents Glyceryl Ethers Phorbol Esters Phospholipid Ethers Protein Kinase C

Authors & Affiliations

6 authors, click to expand affiliations / ORCID

van Blitterswijk W J

Division of Cell Biology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek-Huis), Amsterdam.

van der Bend R L

Kramer I M

Verhoeven A J

Hilkmann H

de Widt J

References (20)

20 references, click to expand

Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
Nature. 1970 Aug 15;227(5259):680-5 PMID: 5432063
Stereospecificity of diacylglycerol for stimulus-response coupling in platelets.
Biochem Biophys Res Commun. 1986 Nov 14;140(3):1143-51 PMID: 3778485
Antiinvasive effect of racemic 1-O-octadecyl-2-O-methylglycero-3-phosphocholine on MO4 mouse fibrosarcoma cells in vitro.
Cancer Res. 1985 Jan;45(1):351-7 PMID: 4038380
Cytotoxicity and metabolism of alkyl phospholipid analogues in neoplastic cells.
Cancer Res. 1986 Nov;46(11):5803-9 PMID: 3756924
Influence of implantation site of MO4 cell aggregates on the formation of metastases.
Invasion Metastasis. 1982;2(1):51-60 PMID: 7188391
Polyclonal antibodies to phospholipid/Ca2+-dependent protein kinase and immunocytochemical localization of the enzyme in rat brain.
Proc Natl Acad Sci U S A. 1985 May;82(9):3030-4 PMID: 3157996
Calculator programs for computing the composition of the solutions containing multiple metals and ligands used for experiments in skinned muscle cells.
J Physiol (Paris). 1979;75(5):463-505 PMID: 533865
Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.
J Clin Invest. 1982 Oct;70(4):699-706 PMID: 6956584
Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells.
J Biol Chem. 1986 Jul 5;261(19):8597-600 PMID: 3013856
Calcium-activated, phospholipid-dependent protein kinase (protein kinase C) from rat brain.
Methods Enzymol. 1983;99:288-98 PMID: 6316094
The nature of protein kinase C activation by physically defined phospholipid vesicles and diacylglycerols.
J Biol Chem. 1985 Sep 5;260(19):10819-25 PMID: 3161882
Diacylglycerols mimic phorbol diester induction of leukemic cell differentiation.
Proc Natl Acad Sci U S A. 1985 Feb;82(3):815-9 PMID: 3156372
Resolution of diacylglycerol moieties of natural glycerophospholipids by gas-liquid chromatography on polar capillary columns.
Can J Biochem. 1982 Jun;60(6):638-50 PMID: 6889454
Calcium-activated, phospholipid-dependent protein kinase from rat brain. Subcellular distribution, purification, and properties.
J Biol Chem. 1982 Nov 25;257(22):13341-8 PMID: 7142151
A simple method for the isolation and purification of total lipides from animal tissues.
J Biol Chem. 1957 May;226(1):497-509 PMID: 13428781
Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture.
Nature. 1977 Nov 24;270(5635):347-9 PMID: 271272
Rigid plasma-membrane-derived vesicles, enriched in tumour-associated surface antigens (MLr), occurring in the ascites fluid of a murine leukaemia (GRSL).
Int J Cancer. 1979 Jan 15;23(1):62-70 PMID: 83306
Phospholipid-sensitive Ca2+-dependent protein phosphorylation system in various types of leukemic cells from human patients and in human leukemic cell lines HL60 and K562, and its inhibition by alkyl-lysophospholipid.
Cancer Res. 1983 Jun;43(6):2955-61 PMID: 6850605
Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion.
Lipids. 1987 Nov;22(11):820-3 PMID: 3444372
The role of protein kinase C in transmembrane signalling.
Annu Rev Cell Biol. 1986;2:149-78 PMID: 3548765

Article Info

Journal

Lipids

Abbr.

Lipids

ISSN

0024-4201

DOI

10.1007/BF02535541

Published

1987-11-00

Pages

842-6

Language

English

Region

United States

NLM ID

0060450

Subset

External Links

PubMed source DOI: 10.1007/BF02535541 View journal details

Analysis Services

A metabolite of an antineoplastic ether phospholipid may inhibit transmembrane signalling via protein kinase C.

Contact

WeChat Official Account