title: The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway.
abstract: The ether phospholipid edelfosine is the prototype of a group of synthetic antitumor alkyllysophospholipid (ALP) compounds that exert pro-apoptotic effects in various types of cancer cells through cell type-dependent mechanisms. In this study, we examined the antitumor effect of edelfosine in human gastric cancer cells. Edelfosine decreased cell viability and induced autophagic death at a moderate concentration (~30 μM), whereas it induced apoptotic cell death at concentrations over 30 μM. Interestingly, low concentrations of edelfosine (5-10 μM) effectively enhanced recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (rhTRAIL/TNFSF10)-induced apoptosis and clonogenicity in gastric cancer cells, including TRAIL-resistant AGS cells. Edelfosine upregulated the protein level of death receptor 5 (DR5/TNFRSF10B) and/or increased DR5 upregulation in lipid rafts. In addition, edelfosine-mediated rhTRAIL sensitization was regulated by the DR5 pathway. Edelfosine also activated p38MAPK (MAPK14), and edelfosine-mediated rhTRAIL sensitization was partially regulated by a p38-mediated decrease in mitochondrial membrane potential. This study suggests a novel therapeutic strategy targeting gastric cancer cells by using the combination of edelfosine and TRAIL.
authors.affiliation: Department of Pathology, College of Medicine, Chosun University, Gwangju, 61501, Korea.|Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea.
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea.
authors.forename: Keshab Raj
authors.initials: KR
authors.lastname: Parajuli
authors.affiliation: Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea. sihan@chosun.ac.kr.|Division of Premedical Science, College of Medicine, Chosun University, Gwangju, 61501, Korea. sihan@chosun.ac.kr.
authors.forename: Song Iy
authors.initials: SI
authors.lastname: Han
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D048308:Mitogen-Activated Protein Kinase 14 / Q000096:biosynthesis* / Q000235:genetics; D010742:Phospholipid Ethers / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D010742:Phospholipid Ethers; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C026659:edelfosine; D048308:Mitogen-Activated Protein Kinase 14
keywords: Alkyllysophospholipid; Apoptosis; Edelfosine; Gastric cancer; TRAIL