Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapy-resistant tumours and how to overcome their emergence. The current study examin...

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Bibliographic Details
Published in:	Cell stress & chaperones Vol. 17; no. 6; pp. 765 - 778
Main Authors:	Lang, B. J., Nguyen, L., Nguyen, H. C., Vieusseux, J. L., Chai, R. C. C., Christophi, C., Fifis, T., Kouspou, M. M., Price, John T.
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer 01-11-2012 Springer Netherlands Springer Nature B.V
Subjects:	Animals Biochemistry Biomedical and Life Sciences Biomedicine Cadherins Cadherins - metabolism Cancer Cancer Research Cell Biology Cell Line, Tumor Cell lines Cell Movement DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Epithelial cells Epithelial-Mesenchymal Transition Heat Shock Transcription Factors Heat stress disorders Heat-Shock Proteins HSP110 Heat-Shock Proteins - metabolism HSP27 Heat-Shock Proteins - metabolism HSP70 Heat-Shock Proteins - metabolism Humans Immunohistochemistry Immunology Mice Molecular Chaperones Neoplasia Neurosciences Original Paper Oxidative stress Phenotypes RNA Interference RNA, Small Interfering - metabolism Shock heating Temperature Transcription Factors - antagonists & inhibitors Transcription Factors - genetics Transcription Factors - metabolism Tumor cell line Epithelial–mesenchymal transition Heat shock factor 1 Proteasome inhibition Cell migration Heat shock
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Summary:	Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapy-resistant tumours and how to overcome their emergence. The current study examines the concept that tumour cell exposure to acute proteotoxic stress results in the acquisition of a more advanced and aggressive cancer cell phenotype. Specifically, we determined whether heat stress resulted in an epithelial-to-mesenchymal transition (EMT) and/or the enhancement of cell migration, components of an advanced and therapeutically resistant cancer phenotype. We identified that heat stress enhanced cell migration in both the lung A549, and breast MDA-MB-468 human adenocarcinoma cell lines, with A549 cells also undergoing a partial EMT. Moreover, in an in vivo model of thermally ablated liver metastases of the mouse colorectal MoCR cell line, immunohistological analysis of classical EMT markers demonstrated a shift to a more mesenchymal phenotype in the surviving tumour fraction, further demonstrating that thermal stress can induce epithelial plasticity. To identify a mechanism by which thermal stress modulates epithelial plasticity, we examined whether the major transcriptional regulator of the heat shock response, heat shock factor 1 (HSF1), was a required component. Knockdown of HSF1 in the A549 model did not prevent the associated morphological changes or enhanced migratory profile of heat stressed cells. Therefore, this study provides evidence that heat stress significantly impacts upon cancer cell epithelial plasticity and the migratory phenotype independent of HSF1. These findings further our understanding of novel biological downstream effects of heat stress and their potential independence from the classical heat shock pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1355-8145 1466-1268
DOI:	10.1007/s12192-012-0349-z