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. 2006 May;207(2):562-9.
doi: 10.1002/jcp.20599.

Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis

Sara Khalil  1 , Jason Luciano, Wenjun Chen, Alice Y-C Liu
Affiliations

Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis

Sara Khalil et al. J Cell Physiol. 2006 May.

Abstract

The objective of this study is to better define induction of the heat shock response by arsenite, and to evaluation if induction of heat shock proteins (HSPs) contributes to the carcinogenic activity of arsenite. We show here that arsenite is a ubiquitous inducer of the heat shock response in mammalian cells: that it activated heat shock transcription factor 1 (HSF1) DNA-binding activity, enhanced hsp 70 promoter, and induced hsp70mRNA and synthesis of HSP chaperones. Using a high throughput hsp70 promoter-luciferase reporter assay, we observed a hormetic dose response where low concentrations of arsenite stimulated and high concentrations inhibited. Further, the response was time-dependent such that with longer times of incubation, the dose response shifted to the left. The effect of arsenite in inducing the hsp 70-luciferase reporter absolutely required a functional HSF1 as it was not observed in HSF1 minus cells but re-instated by expression of HSF1. Consistent with the suggestion that arsenic targets vicinal cysteine-SH, we showed that dithiothreitol blocked the effect of arsenite. Assays of cell viability and caspase showed that arsenite caused a dose-dependent increase in cell death by activation of caspase 3/7 and pre-induction of HSPs blunted these effects. Using anchorage independent cell growth as a late stage tumor promotion assay, we showed that low concentrations of arsenite had a growth promoting effect, which was enhanced by moderate heat shock. Our study provides evidence that induction of the heat shock response is a sensitive biomarker of arsenic exposure and that induction of HSPs likely contributes to the tumor promotion effect of arsenic.

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