Synthetic alkyl-
lysophospholipids represent a family of promising anticancer drugs that induce apoptosis in a variety of
tumor cells. Here we have found a differential subcellular distribution of the alkyl-
lysophospholipid edelfosine in leukemic and solid
tumor cells that leads to distinct anticancer responses.
Edelfosine induced rapid apoptosis in human leukemic cells, including
acute T-cell leukemia Jurkat and Peer cells, but promoted a late apoptotic response, preceded by G(2)/M arrest, in human solid
tumor cells such as cervix epitheloid
carcinoma HeLa cells and lung
carcinoma A549 cells.
c-Jun amino-terminal kinase (JNK) and
caspase-3 were accordingly activated at earlier times in
edelfosine-treated Jurkat cells as compared with
drug-treated HeLa cells. Both leukemic and solid
tumor cells took up this alkyl-
lysophospholipid and expressed the two putative
edelfosine targets, namely cell surface Fas
death receptor (also known as APO-1 or CD95) and endoplasmic reticulum
CTP: phosphocholine cytidylyltransferase. However,
edelfosine was mainly located to plasma membrane
lipid rafts in Jurkat and Peer leukemic cells and to endoplasmic reticulum in solid
tumor HeLa and A549 cells.
Edelfosine induced translocation of Fas, Fas-associated death domain-containing
protein, and JNK into membrane rafts in Jurkat cells, but not in HeLa cells. In contrast,
edelfosine inhibited
phosphatidylcholine biosynthesis in both HeLa and A549 cells, but not in Jurkat or Peer leukemic cells, before the triggering of apoptosis. These data indicate that
edelfosine targets two different subcellular structures in a cell type-dependent manner, namely cell surface
lipid rafts in leukemic cells and endoplasmic reticulum in solid
tumor cells.