Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors.

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.

• Authors: Vikas Dudeja, Rohit K Chugh, Veena Sangwan, Steven J Skube, Nameeta R Mujumdar, Mara B Antonoff, Rajinder K Dawra, Selwyn M Vickers, Ashok K Saluja
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 300 Issue 6 Pg. G948-55 (Jun 2011) ISSN: 1522-1547 [Electronic] United States
• PMID: 21330448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Annexin A5
• DNA-Binding Proteins
• HSF1 protein, human
• Heat Shock Transcription Factors
• Transcription Factors
• CASP3 protein, human
• Caspase 3

Topics

• Annexin A5 (metabolism)
• Apoptosis
• Bile Duct Neoplasms (genetics, metabolism, pathology)
• Bile Ducts, Intrahepatic (metabolism, pathology)
• Blotting, Western
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival
• Cholangiocarcinoma (genetics, metabolism, pathology)
• DNA-Binding Proteins (genetics, metabolism)
• Heat Shock Transcription Factors
• Heat-Shock Response (genetics)
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• RNA Interference
• Signal Transduction
• Time Factors
• Transcription Factors (genetics, metabolism)