Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

Abstract

Background/Aims: 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-κB. 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-κB and downregulation of NF-κB 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.

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

“…Previously, we and others showed that inhibition of survivin by YM155 is effective in vitro in several other malignancies, including squamous cell carcinoma, gastrointestinal stromal tumor, and chondrosarcoma [20], [46], [47]. Evaluation of the effect of YM155 in in vivo models for gastric carcinoma and osteosarcoma demonstrated a suppression of tumor growth in mice [48], [49].…”

Survivin as a novel target protein for reducing the proliferation of cancer cells (Review)

“…YM155 inhibits survivin and also mediates the expression of major genes, including death receptor signaling and tumor necrosis factor receptor 1 signaling factors, that serve a role in apoptosis induction via the extrinsic apoptotic pathway (67). YM155 may have potential as an effective inhibitor of nuclear factor-κB and its downstream target gene matrix metalloproteinase-9, which in turn inhibits the growth, invasion and metastasis of survivin-enriched oral squamous cell carcinoma cells (68). Furthermore, YM155 does not affect normal tissues (55); in in phase I studies, YM155 was demonstrated to be tolerable in patients with advanced cancer, as well as exhibiting anti-tumor activity in patients with non-Hodgkin's lymphoma and hereditary papillary renal carcinoma (69,70).…”

NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN

“…Cell invasion assays were performed as previously described [29,30]. Prior to beginning the experiment, filters were precoated with Matrigel.…”