Abstract
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Original language | English |
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Pages (from-to) | 463-468 |
Number of pages | 6 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 491 |
Issue number | 2 |
DOIs | |
State | Published - Sep 16 2017 |
Bibliographical note
Publisher Copyright:© 2017 Elsevier Inc.
Funding
We thank Karen Martin for her aid in manuscript preparation. Flow Cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404).
Funders | Funder number |
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Vanderbilt Digestive Disease Research Center | DK058404 |
National Childhood Cancer Registry – National Cancer Institute | T32CA106183 |
Vanderbilt Ingram Cancer Center | P30 CA68485 |
Keywords
- Apoptosis
- Epithelial-to-mesenchymal transition
- Ewing sarcoma
- Isoxazole
- ML327
- TRAIL
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology