Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells.
OBJECTIVE
Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. Survivin protein plays critical roles in oral squamous cell carcinoma (OSCC), suggesting that YM155 would be extremely valuable for OSCC. In this study, we tested our hypothesis whether YM155 could be an effective inhibitor of cell growth, invasion and angiogenesis in oral squamous cell carcinoma (OSCC) cells.


METHODS
SCC9 and SCC25 were treated with different concentration of YM155 for indicated time. Using MTT assay and flow cytometry analysis to detect cell growth and apoptosis; Using transwell and Wound healing assay to detect migration and invasion; Using reverse transcription-PCR, Western blotting and electrophoretic mobility shift assay for measuring gene and protein expression, and DNA binding activity of NF-x03BA;B.


RESULTS
YM155 inhibited survivin-rich expressed SCC9 cell growth in a dose- and time dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-x03BA;B and downregulation of NF-x03BA;B downstream genes MMP-9, resulting in the inhibition of SCC9 cell migration and invasion in vitro and caused antitumor activity and anti metastasis in vivo. YM155 treatment did not affect cell growth, apoptosis and invasion of surviving-poor expressed SCC25 cells in vitro.


CONCLUSIONS
YM155 is a potent inhibitor of progression of SCC9 cells, which could be due to attenuation of survivin signaling processes. Our findings provide evidence showing that YM155 could act as a small molecule survivin inhibitor on survivin-rich expressed SCC9 cells in culture as well as when grown as tumor in a xenograft model. We also suggest that survivin could be further developed as a potential therapeutic agent for the treatment of survivin-rich expressed OSCC.
Wei
W
Zhang
Yuan
Y
Liu
Yu Feng
YF
Li
Yun
Y
Yue
Xinghua
X
Yang
Lin
L
Peng
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D016513:Mice, SCID; D009055:Mouth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium