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J Biol Chem, Vol. 273, Issue 18, 11025-11031, May 1, 1998
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From the The prototype of a new class of antiproliferative
phospholipid analogs, hexadecylphosphocholine (HePC), has been shown to inhibit tumor growth and is currently used for the treatment of cutaneous metastases of mammary carcinomas. Although several cellular targets of HePC, e.g. protein kinase C and
CTP:phosphocholine cytidylyltransferase, have been proposed, the
mechanisms of HePC-induced anticancer activity are still unclear.
Considering that the antiproliferative effect of HePC correlates with
inhibition of phosphatidylcholine biosynthesis, which is tightly
coupled to sphingomyelin biosynthesis, we tested the hypothesis that
treatment of cells with the anticancer drug leads to increased cellular
ceramide and subsequently to apoptotic cell death. In the present
study, we showed that 25 µmol/liter HePC induced apoptosis. In
further experiments, we demonstrated that HePC inhibited the
incorporation of radiolabeled choline into phosphatidylcholine and at a
later time point into sphingomyelin. This was confirmed by metabolic
labeling of the lipid backbone using radiolabeled serine, and it was
shown that HePC decreased the incorporation of serine into
sphingomyelin by 35% and simultaneously increased the incorporation of
serine into ceramide by 70%. Determination of the amount of ceramide revealed an increase of 53% in HePC-treated cells compared with controls. In accordance with the hypothesis that elevated ceramide levels may be the missing link between the metabolic effects of HePC
and its proapoptotic properties, HePC-induced apoptosis was blocked by
fumonisin B1, an inhibitor of ceramide synthesis.
Furthermore, we found that membrane-permeable ceramides additively
increased the apoptotic effect of HePC.
Department of Dermatology and
§ Institute of Molecular Biology and Biochemistry,
University Medical Center Benjamin Franklin, The Free University of
Berlin, 12200 Berlin, Germany
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