title: Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis.
abstract: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells while leaving normal cells unharmed, making it a desirable anticancer target. In the present study, metastatic melanoma cell lines were treated with lexatumumab (Human Genome Sciences, Inc.) a high-affinity monoclonal antibody agonistic to TRAIL receptor 2 (DR5). Binding of the antibody to the receptor led to activation of the extrinsic apoptosis pathway in approximately 20% of the treated cells. However, by combining subtoxic concentrations of the protein translation inhibitor anisomycin with lexatumumab, we obtained synergistic effects on cell viability compared with single agent treatment. Even the low doses of anisomycin could inhibit protein synthesis in melanoma cells with up to 30%, which might result in the shift in the levels of the proteins involved in apoptosis. Co-treatment with anisomycin increased activation of caspases and cleavage of the anti-apoptotic protein Livin, leading to formation of truncated p30-Livin α and p28-Livin β proteins with potential pro-apoptotic functions. Furthermore, ansiomcycin treatment decreased levels of antiapototic XIAP. In summary our results suggest that combinational treatment with anicomycin and lexatumumab represents a novel therapeutic strategy in the treatment of melanoma.
authors.affiliation: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. ana.slipicevic@rr-research.no
authors.forename: Ana
authors.initials: A
authors.lastname: Slipicevic
authors.forename: Geir Frode
authors.initials: GF
authors.lastname: Øy
authors.forename: Anne Katrine Ree
authors.initials: AK
authors.lastname: Rosnes
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Stakkestad
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Emilsen
authors.forename: Birgit
authors.initials: B
authors.lastname: Engesæter
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
mesh_terms: D000841:Anisomycin / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000841:Anisomycin; C510234:lexatumumab