Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 16, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s12967-018-1451-5
Keywords
Epithelial-mesenchymal transition; Glioblastoma; Radiation; STAT3; YM155
Categories
Funding
- Natural Science Foundation of China [81572487, 81402060]
- Special Foundation for Taishan Scholars [tshw201502056]
- Department of Science & Technology of Shandong Province [2015ZDXX0801A01, 2014kjhm0101]
- Shandong Provincial Outstanding Medical Academic Professional Program
- Fundamental Research Funds of Shandong University [2016JC019]
- Stiftelsen Kristian Gerhard Jebsen
- The Norwegian Cancer Society
- Norwegian Research Council
- Norwegian Centre for International Cooperation in Education (SIU) [UTF-2014/10047]
- Helse Vest
- Haukeland Hospital
Ask authors/readers for more resources
Background: Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines. Methods: GBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response. Results: YM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals. Conclusions: YM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available