Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway
| Autor: | Jeffrey A. Toretsky, Kamal P. Sajwan, Lymor Ringer, Metin Ozdemirli, Olga Rodriguez, Tobey J. MacDonald, Gülay Bulut, Michael D. Hall, Daniel Peaceman, Chris Albanese, Aykut Üren, Elspeth M. Beauchamp, Yichien Lee |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Antineoplastic Agents
Sarcoma Ewing Biology Models Biological Zinc Finger Protein GLI1 Arsenicals Receptors G-Protein-Coupled chemistry.chemical_compound Mice Arsenic Trioxide GLI1 Cell Line Tumor Neoplasms Animals Humans Hedgehog Proteins Arsenic trioxide Hedgehog Transcription factor Oncogene integumentary system Cell growth Oxides General Medicine Smoothened Receptor Transplantation chemistry Immunology biology.protein Cancer research Signal transduction Research Article Medulloblastoma Signal Transduction Transcription Factors |
| Popis: | The Hedgehog (Hh) pathway is activated in some human cancers, including medulloblastoma. The glioma-associated oncogene homolog (GLI) transcription factors are critical mediators of the activated Hh pathway, and their expression may be elevated in some tumors independent of upstream Hh signaling. Thus, therapies targeting GLI transcription factors may benefit a wide spectrum of patients with mutations at different nodal points of the Hh pathway. In this study, we present evidence that arsenic trioxide (ATO) suppresses human cancer cell growth and tumor development in mice by inhibiting GLI1. Mechanistically, ATO directly bound to GLI1 protein, inhibited its transcriptional activity, and decreased expression of endogenous GLI target genes. Consistent with this, ATO inhibited the growth of human cancer cell lines that depended on upregulated GLI expression in vitro and in vivo in a xenograft model of Ewing sarcoma. Furthermore, ATO improved survival of a clinically relevant spontaneous mouse model of medulloblastoma with activated Hh pathway signaling. Our results establish ATO as a Hh pathway inhibitor acting at the level of GLI1 both in vitro and in vivo. These results warrant the clinical investigation of ATO for tumors with activated Hh/GLI signaling, in particular patients who develop resistance to current therapies targeting the Hh pathway upstream of GLI. |
| Databáze: | OpenAIRE |
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