Activation of Hedgehog Signaling by the Environmental Toxicant Arsenic May Contribute to the Etiology of Arsenic-Induced Tumors

Exposure to the environmental toxicant arsenic, through both contaminated water and food, contributes to significant health problems worldwide. In particular, arsenic exposure is thought to function as a carcinogen for lung, skin and bladder cancer, via mechanisms that remain largely unknown. More recently, the Hedgehog (HH) signaling pathway has also been implicated in the progression and maintenance of these same cancers. Based on these similarities, we tested the hypothesis that arsenic may act in part through activating HH signaling. Here, we show that arsenic is able to activate HH signaling in a number of primary and established tissue culture cells, as well as in vivo. Arsenic activates HH signaling by decreasing the stability of the repressor form of GLI3, one of the transcription factors that ultimately regulate HH activity. We also show, using tumor samples from a cohort of bladder cancer patients, that high levels of arsenic exposure are associated with high levels of HH activity. Given the important role HH signaling plays in the maintenance and progression of a variety of tumors, including bladder cancer, these results suggest that arsenic exposure may in part promote cancer through the activation of HH signaling. Thus, we provide an important insight into the etiology of arsenic induced human carcinogenesis, which may be relevant to millions of people exposed to high levels of arsenic worldwide.