RRC ID 44531
Author Nakamura S, Nagano S, Nagao H, Ishidou Y, Yokouchi M, Abematsu M, Yamamoto T, Komiya S, Setoguchi T.
Title Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation.
Journal PLoS One
Abstract The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma.
Volume 8(7)
Pages e69466
Published 2013-1-1
DOI 10.1371/journal.pone.0069466
PII PONE-D-13-01279
PMID 23861973
PMC PMC3704531
MeSH Animals Apoptosis / drug effects Apoptosis / genetics Arsenic Trioxide Arsenicals / pharmacology* Arsenicals / therapeutic use Cell Line, Tumor Cell Proliferation / drug effects Cisplatin / pharmacology DNA Damage / genetics* Hedgehog Proteins / metabolism Humans Mice Osteosarcoma / drug therapy Osteosarcoma / genetics Osteosarcoma / pathology Oxides / pharmacology* Oxides / therapeutic use Signal Transduction / drug effects Signal Transduction / genetics Transcription Factors / genetics* Transcription Factors / metabolism Transcription, Genetic / drug effects* Zinc Finger Protein GLI1
IF 2.74
Times Cited 47
Human and Animal Cells HS-Os-1(RCB2229)