Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells.
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.
Nieto-Miguel
Teresa
T
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Gajate
Consuelo
C
Mollinedo
Faustino
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000737:chemistry*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D021962:Membrane Microdomains; D009369:Neoplasms / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; D008246:Lysophospholipids; D010742:Phospholipid Ethers; D019014:fas Receptor; C026659:edelfosine; D048670:MAP Kinase Kinase 4; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases