Journal article
Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors
American journal of physiology: Gastrointestinal and liver physiology, Vol.300(6), pp.G948-G955
06/01/2011
DOI: 10.1152/ajpgi.00346.2010
PMID: 21330448
Abstract
Several mechanisms have evolved to ensure the survival of cells under adverse conditions. The heat shock response is one such evolutionarily conserved survival mechanism. Heat shock factor-1 (HSF1) is a transcriptional regulator of the heat shock response. By the very nature of its prosurvival function, HSF1 may contribute to the pathogenesis of cancer. The current study investigates the role of HSF1 in the pathogenesis of pancreatobiliary tumors. HSF1 was downregulated in pancreatic cancer (MIA PaCa-2 and S2-013) and cholangiocarcinoma (KMBC and KMCH) cell lines by HSF1-specific small interfering RNA (siRNA). Nonsilencing siRNA was used as control. The effect of HSF1 downregulation on viability and apoptosis parameters, i.e., annexin V, terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling (TUNEL), and caspase-3, was measured. To evaluate the cancer-specific effects of HSF1, the effect of HSF1 downregulation on normal human pancreatic ductal cells was also evaluated. HSF1 is abundantly expressed in human pancreatobiliary cancer cell lines, as well as in pancreatic cancer tissue, as demonstrated by Western blot and immunohistochemistry, respectively. Inhibition of HSF1 expression by the HSF1 siRNA sequences leads to time-dependent death in pancreatic and cholangiocarcinoma cell lines. Downregulation of HSF1 expression induces annexin V and TUNEL positivity and caspase-3 activation, suggesting activation of a caspase-dependent apoptotic pathway. Although caspase-3 inhibition protects against cell death induced by HSF1 expression, it does not completely prevent it, suggesting a role for caspase-independent cell death. HSF1 plays a prosurvival role in the pathogenesis of pancreatobiliary tumors. Modulation of HSF1 activity could therefore emerge as a novel therapeutic strategy for cancer treatment.
Details
- Title: Subtitle
- Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors
- Creators
- Vikas Dudeja - University of MinnesotaRohit K. Chugh - University of MinnesotaVeena Sangwan - University of MinnesotaSteven J. Skube - University of MinnesotaNameeta R. Mujumdar - University of MinnesotaMara B. Antonoff - University of MinnesotaRajinder K. Dawra - University of MinnesotaSelwyn M. Vickers - University of MinnesotaAshok K. Saluja - University of Minnesota
- Resource Type
- Journal article
- Publication Details
- American journal of physiology: Gastrointestinal and liver physiology, Vol.300(6), pp.G948-G955
- DOI
- 10.1152/ajpgi.00346.2010
- PMID
- 21330448
- NLM abbreviation
- Am J Physiol Gastrointest Liver Physiol
- ISSN
- 0193-1857
- eISSN
- 1522-1547
- Publisher
- Amer Physiological Soc
- Number of pages
- 8
- Grant note
- P50CA101955 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01DK093047 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) CA-124723; DK-058694 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 06/01/2011
- Academic Unit
- Anatomy and Cell Biology; Surgery
- Record Identifier
- 9985244680102771
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