title: Survivin is a viable target for the treatment of malignant peripheral nerve sheath tumors.
abstract: OBJECTIVE
  To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST) EXPERIMENTAL DESIGN: Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied in vitro and in vivo; real-time PCR, Western blotting, and immunocytochemical analyses were used to evaluate survivin expression and localization activation. Cell culture assays were used to evaluate the impact of anti-survivin-specific siRNA inhibition on cell growth and cell-cycle progression and survival. The effect of the small-molecule survivin inhibitor YM155 on local and metastatic MPNST growth was examined in vivo.
  
  
  RESULTS
  Survivin was found to be highly expressed in human MPNSTs; enhanced cytoplasmic subcellular localization differentiated MPNSTs from their plexiform neurofibroma premalignant counterparts. Human MPNST cell lines exhibited survivin mRNA and protein overexpression; expression in both nuclear and cytoplasmic compartments was noted. Survivin knockdown abrogated MPNST cell growth, inducing G(2) cell-cycle arrest and marked apoptosis. YM155 inhibited human MPNST xenograft growth and metastasis in severe combined immunodeficient (SCID) mice. Antitumor effects were more pronounced in fast-growing xenografts.
  
  
  CONCLUSIONS
  Our studies show an important role for survivin in human MPNST biology. Patients with MPNSTs should be considered for ongoing or future clinical trials that evaluate anti-survivin therapeutic strategies. Most importantly, future investigations should evaluate additional pathways that can be targeted in combination with survivin for maximal synergistic anti-MPNST effects.
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Ghadimi
authors.forename: Eric D
authors.initials: ED
authors.lastname: Young
authors.forename: Roman
authors.initials: R
authors.lastname: Belousov
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.forename: Kristelle
authors.initials: K
authors.lastname: Lusby
authors.forename: Christine
authors.initials: C
authors.lastname: Kivlin
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Demicco
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D016513:Mice, SCID; D009285:Naphthoquinones / Q000627:therapeutic use*; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077022:Survivin; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; C523798:sepantronium