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.