ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Eric J. Rellinger, Chandrasekhar Padmanabhan, Jingbo Qiao, Andrew Appert, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp, Dai H. Chung

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 languageEnglish
Pages (from-to)463-468
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume491
Issue number2
DOIs
StatePublished - 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).

FundersFunder number
Vanderbilt Digestive Disease Research CenterDK058404
National Childhood Cancer Registry – National Cancer InstituteT32CA106183
Vanderbilt Ingram Cancer CenterP30 CA68485

    Keywords

    • Apoptosis
    • Epithelial-to-mesenchymal transition
    • Ewing sarcoma
    • Isoxazole
    • ML327
    • TRAIL

    ASJC Scopus subject areas

    • Biophysics
    • Biochemistry
    • Molecular Biology
    • Cell Biology

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