title: Clusterin regulates drug-resistance in melanoma cells.
abstract: Clusterin has recently been shown to act as an antiapoptotic protein that confers drug-resistance in models of epithelial tumors. The aim of our work was to provide an insight into a possible role of clusterin in the regulation of drug-resistance in melanoma. In tissue samples, clusterin expression was low in nevi, but high in primary melanoma and melanoma metastases. Clusterin was also strongly expressed in melanoma cell lines, but was barely detectable in cultured melanocytes. To elucidate a possible role of clusterin in drug-resistance of melanoma, clusterin expression was regulated by either plasmid-driven overexpression or by antisense-mediated downregulation. Clusterin overexpression was associated with an increase in drug-resistance, i.e., with an increased survival of melanoma cells in the presence of cytotoxic drugs. In contrast, downregulation of clusterin by 2'-O-(2-methoxy)ethyl (2'MOE)-modified antisense oligonucleotides (AS-ODN) directed against clusterin mRNA significantly reduced drug-resistance, i.e., decreased survival of melanoma cells in the presence of cytotoxic drugs. To evaluate the effects of clusterin-antisense treatment in vivo, we applied an SCID-mouse/human-melanoma xenotransplantation model. Pre-treatment of mice with the 2'MOE-modified clusterin AS-ODN was associated with a significantly improved tumor response to dacarbazine as compared with animals pretreated with a scrambled control oligonucleotide. Taken together, we show that clusterin is strongly expressed in melanoma. Downregulation of clusterin reduces drug-resistance, i.e., reduces melanoma cell survival in response to cytotoxic drugs in vitro and in vivo. Thus, reducing clusterin expression may provide a novel tool to overcome drug-resistance in melanoma.
authors.affiliation: Department of Dermatology, Division of General Dermatology and Medical University Vienna, Vienna, Austria. christoph.hoeller@univie.ac.at
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoeller
authors.forename: Barbara
authors.initials: B
authors.lastname: Pratscher
authors.forename: Christiane
authors.initials: C
authors.lastname: Thallinger
authors.forename: Dorian
authors.initials: D
authors.lastname: Winter
authors.forename: Dieter
authors.initials: D
authors.lastname: Fink
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Burkhard
authors.initials: B
authors.lastname: Jansen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D051152:Clusterin; D003606:Dacarbazine / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D003606:Dacarbazine