Differential Targets and Subcellular Localization of Antitumor Alkyl-lysophospholipid in Leukemic Versus Solid Tumor Cells

Faustino Mollinedo,Teresa Nieto-Miguel,Consuelo Gajate

doi:10.1074/jbc.m511251200

Abstract

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.

Highlights

We report that edelfosine shows two different subcellular localizations, namely in plasma membrane lipid rafts and endoplasmic reticulum, in a cell type-dependent manner, affecting two distinct targets and leading to apoptosis through different signaling mechanisms in human leukemic and solid tumor cells
Edelfosine triggered a persistent activation of Jun amino-terminal kinase (JNK), a signaling pathway required for edelfosine-induced apoptosis [28, 29], before the onset of apoptosis in both leukemic Jurkat cells and solid tumor HeLa cells (Fig. 1B)
In this study we have found that the antitumor alkyl-lysophospholipid edelfosine is differentially compartmentalized in leukemic and solid tumor cells, exerting different biological actions in both cell types that eventually lead to apoptosis

Summary

Introduction

We report that edelfosine shows two different subcellular localizations, namely in plasma membrane lipid rafts and endoplasmic reticulum, in a cell type-dependent manner, affecting two distinct targets and leading to apoptosis through different signaling mechanisms in human leukemic and solid tumor cells. Edelfosine Translocates Fas and Apoptotic Molecules into Membrane Rafts in Leukemic Cells, but Not in Solid Tumor Cells—We have recently reported that edelfosine induces recruitment of Fas death receptor and additional downstream signaling molecules into lipid rafts in leukemic cells, this process being critical for the rapid induction of apoptosis [7].

Results

Conclusion