Arsenic: a potentially useful poison for Hedgehog-driven cancers

Abstract

Dysregulated Hedgehog (Hh) signaling has been implicated in a growing number of human cancers. To date, most antagonists of this signaling pathway that have been developed target the Hh receptor Smoothened. However, these are predicted to have minimal effect when the pathway is activated as a result of dysregulation downstream of this receptor. In this issue of the JCI, Beauchamp and colleagues provide preclinical evidence that arsenic trioxide, a drug FDA approved for the treatment of acute promyelocytic leukemia, inhibits the growth of Ewing sarcoma and medulloblastoma cells by targeting GLI family zinc finger (GLI) proteins, which are Hh signaling pathway components downstream of Smoothened.

Figure 1. Proposed mechanisms of ATO action on Hh signaling pathway components.

The schematic linearly shows activation of Hh signaling after binding of Hh ligand to the Patched (Ptc) receptor. This results in subsequent localization of the Smo transmembrane protein to the primary cilium, where further signal transduction occurs after proteolytic processing of GLI2 to an activator form, resulting in GLI2 nuclear translocation to transcriptionally activate Hh target genes. Smo inhibitors that are currently in clinical trials for human cancers are shown. ATO inhibits GLI1 and GLI2 proteins downstream of the Smo protein through similar, yet slightly distinct, mechanisms of action (13, 18).