Abstract | PURPOSE: 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.
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Authors | Markus P Ghadimi, Eric D Young, Roman Belousov, Yiqun Zhang, Gonzalo Lopez, Kristelle Lusby, Christine Kivlin, Elizabeth G Demicco, Chad J Creighton, Alexander J Lazar, Raphael E Pollock, Dina Lev |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 18
Issue 9
Pg. 2545-57
(May 01 2012)
ISSN: 1557-3265 [Electronic] United States |
PMID | 22407831
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | ©2012 AACR. |
Chemical References |
- BIRC5 protein, human
- Birc5 protein, mouse
- Imidazoles
- Inhibitor of Apoptosis Proteins
- Naphthoquinones
- RNA, Messenger
- RNA, Small Interfering
- Repressor Proteins
- Survivin
- sepantronium
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Topics |
- Adult
- Animals
- Apoptosis
- Blotting, Western
- Cell Cycle
- Cell Proliferation
- Female
- Fluorescent Antibody Technique
- Humans
- Imidazoles
(therapeutic use)
- Immunoenzyme Techniques
- Inhibitor of Apoptosis Proteins
(antagonists & inhibitors, genetics, metabolism)
- Mice
- Mice, Hairless
- Mice, SCID
- Naphthoquinones
(therapeutic use)
- Nerve Sheath Neoplasms
(drug therapy, genetics, metabolism)
- RNA, Messenger
(genetics)
- RNA, Small Interfering
(genetics)
- Real-Time Polymerase Chain Reaction
- Repressor Proteins
(antagonists & inhibitors, genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Schwann Cells
(cytology, drug effects, metabolism)
- Survivin
- Tissue Array Analysis
- Xenograft Model Antitumor Assays
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