Survivin is a viable target for the treatment of malignant peripheral nerve sheath tumors.

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.

• 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)
• 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

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