title: Sequential treatment by ionizing radiation and sodium arsenite dramatically accelerates TRAIL-mediated apoptosis of human melanoma cells.
abstract: Melanoma is the most lethal form of skin cancer. There is a lack of effective treatments for individuals with advanced disease. Many melanomas exhibit high levels of radioresistance. The direct consequence of gamma-irradiation for most melanoma cells is growth arrest at the G2-M phase of cell cycle. However, radiation-induced signaling pathways may affect numerous additional targets in cancer cells. We show in the present study that gamma-irradiation, as well as alpha-particle exposure, dramatically increases the susceptibility of melanoma cells to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via up-regulation of surface TRAIL-receptor 1/receptor 2 (DR4/DR5) levels and to Fas ligand-mediated apoptosis via up-regulation of surface Fas levels. Additionally, increased dynamin-2 expression after irradiation is critically important in the translocation of death receptor to the cell surface. Moreover, sodium arsenite treatment may up-regulate expression of endogenous TRAIL and induces its translocation to cell surface and further down-regulates cFLIP levels in melanoma cells. We have evaluated the effects of sequential gamma-irradiation and arsenite treatment of melanoma cells for the induction of death signaling. Such treatment results in an efficient TRAIL-mediated apoptosis via a paracrine mechanism. These data highlight the efficacy of combined modality treatment involving radiation and arsenite in clinical management of this often fatal form of skin cancer.
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. vni3@columbia.edu
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Ivanov
authors.forename: Hongning
authors.initials: H
authors.lastname: Zhou
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D000512:Alpha Particles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D018053:Arsenites / Q000008:administration & dosage / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D003131:Combined Modality Therapy; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D034285:Dynamin II / Q000096:biosynthesis / Q000378:metabolism; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D017670:Sodium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018053:Arsenites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D017670:Sodium Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C017947:sodium arsenite; D003513:Cycloheximide; D034285:Dynamin II