Targeting hedgehog signaling pathway in pediatric tumors: in vitro evaluation of SMO and GLI inhibitors
Abstract
The successful use of SMO inhibitors in tumors with activating mutations in hedgehog signaling raised interests in their exploitation against other malignancies. The role of hedgehog signaling in pediatric malignancies remains unclear. We investigated the hedgehog signaling and its inhibition in a panel of 18 tumor cell lines derived from six of the most common and highly aggressive pediatric tumor types. None of the cell lines was known to stem from tumors with activating hedgehog mutations. Tetrazolium-based assays (MTT and MTS) and BrdU assays were used to analyze cell viability and proliferation after exposure to SANT1 and GANT61. Expression analysis of hedgehog signaling members and cyclins was performed by quantitative real-time PCR and Western blot. Key members of hedgehog signaling (SHH, PTCH1, SMO, GLI1, GLI2 and SUFU) were expressed in all cell lines. In 50% of the cell lines viability was significantly increased by SHH exposure. Stimulation was not restricted to distinct tumor types, but related to cell lines with higher mRNA levels of PTCH1, SMO, GLI1 and GLI2. SMO inhibition by SANT1 moderately decreased cell viability with GI50s between 28 and 93 µmol/l. Sensitivity to SANT1 was not related to distinct tumor types...Continue Reading
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