Περίληψη:
Chondrosarcomas are malignant cartilage-forming bone tumors, which are
intrinsically resistant to chemo- and radiotherapy, leaving surgical
removal as the only curative treatment option. Therefore, our aim was to
identify genes involved in chondrosarcoma cell survival that could serve
as a target for therapy. siRNA screening for 51 apoptosis-related genes
in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as
essential for chondrosarcoma survival. Using immunohistochemistry,
nuclear as well as cytoplasmic survivin expression was analyzed in 207
chondrosarcomas of different subtypes. Nuclear survivin has been
implicated in cell-cycle regulation while cytoplasmic localization is
important for its anti-apoptotic function. RT-PCR was performed to
determine expression of the most common survivin isoforms. Sensitivity
to YM155, a survivin inhibitor currently in phase I/II clinical trial
for other tumors, was examined in 10 chondrosarcoma cell lines using
viability assay, apoptosis assay and cell-cycle analysis. Survivin
expression was found in all chondrosarcoma patient samples. Higher
expression of nuclear and cytoplasmic survivin was observed with
increasing histological grade in central chondrosarcomas. Inhibition of
survivin using YM155 showed that especially TP53 mutant cell lines were
sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather,
YM155 treatment resulted in a block in S phase in two out of three
chondrosarcoma cell lines, indicating that survivin is more involved in
cell-cycle regulation than in apoptosis. Thus, survivin is important for
chondrosarcoma survival and chondrosarcoma patients might benefit from
survivin inhibition using YM155, for which TP53 mutational status can
serve as a predictive biomarker.
Συγγραφείς:
de Jong, Y.
van Oosterwijk, J. G.
Kruisselbrink, A. B. and
Briaire-de Bruijn, I. H.
Agrogiannis, G.
Baranski, Z. and
Cleven, A. H. G.
Cleton-Jansen, A-M
van de Water, B.
Danen,
E. H. J.
Bovee, J. V. M. G.
