Abstract
Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma.
Highlights
Malignant gliomas are associated with a high mortality rate
Hedgehog signaling is initiated by Sonic Hedgehog (Shh) binding to its receptor[6], patched, which thereby diminishes the inhibitory effects of patched-1 (PTCH1) on smoothened (Smo)
To assess the effect of GDC-0449 on the growth inhibition of glioma cells, four glioma cell lines were treated with GDC-0449 and cell viability was estimated using Cell Counting Kit-8 (CCK8) assay
Summary
Malignant gliomas are associated with a high mortality rate. there is an urgent need for the development of novel targeted therapeutics. GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli[1] and Gli[2]). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. The Hedgehog pathway is a complex signaling cascade that performs crucial functions in cell proliferation, apoptosis and self-renewal[3]. This pathway is inactive in normal human mature cells[4], it is hyper-activated in many tumors[5]. Its underlying action mechanisms have not been investigated in glioma
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