Inhibition of the Heat Shock Response by PI103 Enhances the Cytotoxicity of Arsenic Trioxide
Open Access
- 10 April 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 128 (1), 126-136
- https://doi.org/10.1093/toxsci/kfs130
Abstract
Heat shock factor 1 (HSF1) is a key regulator of the cytoprotective and anti-apoptotic heat shock response and can be activated by arsenite. Inhibition of HSF1 activation may therefore enhance the cytotoxicity of arsenic trioxide (ATO). We show that ATO induced HSF1 phosphorylation at serine 326 (S326) and induced HSF1-dependent expression of heat shock proteins (HSPs) 27 and 70 in cultured cells. HSF1 significantly reduced cell sensitivity to ATO by reducing apoptosis. Disruption of HSF1 function not only reduced ATO induction of HSP27 and 70 but also enhanced ATO cytotoxicity by elevating apoptosis. These results reveal that HSF1 activation and the resulting induction of HSPs may protect cells from ATO cytotoxicity. The diminished expression of HSPs and hypersensitivity to ATO in cells stably depleted of HSF1 was rescued by ectopic expression of wild-type HSF1 but not an S326A substitution mutant, indicating that phosphorylation at S326 was critical for the protective effect of HSF1. Simultaneous treatment of cells with ATO and PI103, an inhibitor of members of the phosphatidylinositol 3-kinase (PI3K) family, suppressed not only ATO-induced expression of an HSP70 promoter-reporter construct and endogenous HSP70 but also phosphorylation of HSF1 S326. PI103 considerably reduced HSF1 transactivation in ATO-treated cells but had only a limited effect on HSF1 nuclear translocation and DNA binding. Furthermore, PI103 enhanced ATO cytotoxicity in an HSF1-dependent manner. Thus, inhibition of S326 phosphorylation by PI103 blocks the transactivation of HSF1 and may consequently suppress ATO induction of the heat shock response and sensitize cells to ATO.Keywords
This publication has 63 references indexed in Scilit:
- High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancerProceedings of the National Academy of Sciences, 2011
- O-Linked β-N-acetylglucosamine (O-GlcNAc) Regulates Stress-induced Heat Shock Protein Expression in a GSK-3β-dependent MannerJournal of Biological Chemistry, 2010
- p27 Suppresses Arsenite-induced Hsp27/Hsp70 Expression through Inhibiting JNK2/c-Jun- and HSF-1-dependent PathwaysJournal of Biological Chemistry, 2010
- Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesisOncogene, 2010
- HSF1-mediated BAG3 Expression Attenuates Apoptosis in 4-Hydroxynonenal-treated Colon Cancer Cells via Stabilization of Anti-apoptotic Bcl-2 ProteinsJournal of Biological Chemistry, 2009
- Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerizationToxicology and Applied Pharmacology, 2008
- Heat Shock Factor 1 Is a Powerful Multifaceted Modifier of CarcinogenesisCell, 2007
- A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in gliomaCancer Cell, 2006
- Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1The EMBO Journal, 2001
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970