Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma.
OBJECTIVE
Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro.


METHODS
An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation.


RESULTS
Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation.


CONCLUSIONS
Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma.
Klinik und Poliklinik für Strahlentherapie -Radioonkologie, Universitätsklinikum Münster, Albert-Schweitzer Campus 1 Gebäude A1, 48149, Münster, Germany. greveb@uni-muenster.de
B
B
Greve
F
F
Sheikh-Mounessi
B
B
Kemper
I
I
Ernst
M
M
Götte
H T
HT
Eich
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D015536:Down-Regulation / Q000235:genetics / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics* / Q000528:radiation effects*; D060888:Real-Time Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000532:radiotherapy*; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin