title: Pigment epithelium-derived factor (PEDF) promotes tumor cell death by inducing macrophage membrane tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
abstract: Pigment epithelium-derived factor (PEDF) is an intrinsic anti-angiogenic factor and a potential anti-tumor agent. The tumoricidal mechanism of PEDF, however, has not been fully elucidated. Here we report that PEDF induces the apoptosis of TC-1 and SK-Hep-1 tumor cells when they are cocultured with bone marrow-derived macrophages (BMDMs). This macrophage-mediated tumor killing is prevented by blockage of TNF-related apoptosis-inducing ligand (TRAIL) following treatment with the soluble TRAIL receptor. PEDF also increases the amount of membrane-bound TRAIL on cultured mouse BMDMs and on macrophages surrounding subcutaneous tumors. PEDF-induced tumor killing and TRAIL induction are abrogated by peroxisome proliferator-activated receptor γ (PPARγ) antagonists or small interfering RNAs targeting PPARγ. PEDF also induces PPARγ in BMDMs. Furthermore, the activity of the TRAIL promoter in human macrophages is increased by PEDF stimulation. Chromatin immunoprecipitation and DNA pull-down assays confirmed that endogenous PPARγ binds to a functional PPAR-response element (PPRE) in the TRAIL promoter, and mutation of this PPRE abolishes the binding of the PPARγ-RXRα heterodimer. Also, PPARγ-dependent transactivation and PPARγ-RXRα binding to this PPRE are prevented by PPARγ antagonists. Our results provide a novel mechanism for the tumoricidal activity of PEDF, which involves tumor cell killing via PPARγ-mediated TRAIL induction in macrophages.
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Tsung-Chuan
authors.initials: TC
authors.lastname: Ho
authors.affiliation: Department of Microbiology, School of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Show-Li
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Mackay Memorial Hospital, Taipei 104, Taiwan; Mackay Medicine, Nursing, and Management College, Taipei 112, Taiwan.
authors.forename: Shou-Chuan
authors.initials: SC
authors.lastname: Shih
authors.affiliation: Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei 104, Taiwan; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Shing-Jyh
authors.initials: SJ
authors.lastname: Chang
authors.affiliation: Centers for Disease Control, Taipei 115, Taiwan; Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Su-Lin
authors.initials: SL
authors.lastname: Yang
authors.affiliation: Mackay Medicine, Nursing, and Management College, Taipei 112, Taiwan; Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Hsieh
authors.affiliation: Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Huey-Chuan
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: Mackay Medicine, Nursing, and Management College, Taipei 112, Taiwan; Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Lee-Jen
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei 104, Taiwan; Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan; Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan. Electronic address: yptsao@yahoo.com.
authors.forename: Yeou-Ping
authors.initials: YP
authors.lastname: Tsao
mesh_terms: D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005136:Eye Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000276:immunology / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000276:immunology; D047490:Retinoid X Receptor alpha / Q000276:immunology / Q000378:metabolism; D015843:Serpins / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D047495:PPAR gamma; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047490:Retinoid X Receptor alpha; D015843:Serpins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099174:Pigment Epithelium-Derived Factor; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse