title: Survivin is a therapeutic target in Merkel cell carcinoma.
abstract: Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing 5)] were up-regulated sevenfold in virus-positive compared to virus-negative MCC tumors. Knockdown of MCV large T antigen in MCV-positive MCC cell lines decreased survivin mRNA and protein expression. Exogenously expressed MCV large T antigen increased survivin protein expression in non-MCC primary cells. This required an intact retinoblastoma protein-targeting domain that activated survivin gene transcription as well as expression of other G(1)-S-phase proteins including E2F1 and cyclin E. Survivin expression is critical to the survival of MCV-positive MCC cells. A small-molecule survivin inhibitor, YM155, potently and selectively initiates irreversible, nonapoptotic, programmed MCV-positive MCC cell death. Of 1360 other chemotherapeutic and pharmacologically active compounds screened in vitro, only bortezomib (Velcade) was found to be similarly potent, but was not selective in killing MCV-positive MCC cells. YM155 halted the growth of MCV-positive MCC xenograft tumors and was nontoxic in mice, whereas bortezomib was not active in vivo and mice displayed serious morbidity. Xenograft tumors resumed growth once YM155 treatment was stopped, suggesting that YM155 may be cytostatic rather than cytotoxic in vivo. Identifying the cellular pathways, such as those involving survivin, that are targeted by tumor viruses can lead to rapid and rational identification of drug candidates for treating virus-induced cancers.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
authors.forename: Reety
authors.initials: R
authors.lastname: Arora
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shuda
authors.forename: Anna
authors.initials: A
authors.lastname: Guastafierro
authors.forename: Huichen
authors.initials: H
authors.lastname: Feng
authors.forename: Tuna
authors.initials: T
authors.lastname: Toptan
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: Laura L
authors.initials: LL
authors.lastname: Vollmer
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D059965:Merkel cell polyomavirus / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009285:Naphthoquinones / Q000494:pharmacology; D027601:Polyomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000628:therapy / Q000821:virology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D057170:Translational Research, Biomedical; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism* / Q000628:therapy / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D001897:Boronic Acids; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D011719:Pyrazines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077022:Survivin; D000069286:Bortezomib; C523798:sepantronium