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

2011 ◽  
Vol 300 (6) ◽  
pp. G948-G955 ◽  
Author(s):  
Vikas Dudeja ◽  
Rohit K. Chugh ◽  
Veena Sangwan ◽  
Steven J. Skube ◽  
Nameeta R. Mujumdar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Heat Shock ◽  
Cell Lines ◽  
Heat Shock Response ◽  
Caspase 3 ◽  
Annexin V ◽  
Heat Shock Factor 1 ◽  
Shock Response

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.

Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts

2006 ◽  
Vol 84 (5) ◽  
pp. 703-712 ◽  
Author(s):  
Silvia Fossati ◽  
Laura Formentini ◽  
Zhao-Qi Wang ◽  
Flavio Moroni ◽  
Alberto Chiarugi
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Heat Shock Factor ◽  
Binding Motif ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

scholarly journals Activation of Heat Shock Genes Is Not Necessary for Protection by Heat Shock Transcription Factor 1 against Cell Death Due to a Single Exposure to High Temperatures

2003 ◽  
Vol 23 (16) ◽  
pp. 5882-5895 ◽  
Author(s):  
Sachiye Inouye ◽  
Kensaku Katsuki ◽  
Hanae Izu ◽  
Mitsuaki Fujimoto ◽  
Kazuma Sugahara ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Heat Shock Response ◽  
Single Exposure ◽  
Heat Shock Genes ◽  
Amino Terminal ◽  
Shock Response ◽  
Shock Proteins

ABSTRACT Heat shock response, which is characterized by the induction of a set of heat shock proteins, is essential for induced thermotolerance and is regulated by heat shock transcription factors (HSFs). Curiously, HSF1 is essential for heat shock response in mammals, whereas in avian HSF3, an avian-specific factor is required for the burst activation of heat shock genes. Amino acid sequences of chicken HSF1 are highly conserved with human HSF1, but those of HSF3 diverge significantly. Here, we demonstrated that chicken HSF1 lost the ability to activate heat shock genes through the amino-terminal domain containing an alanine-rich sequence and a DNA-binding domain. Surprisingly, chicken and human HSF1 but not HSF3 possess a novel function that protects against a single exposure to mild heat shock, which is not mediated through the activation of heat shock genes. Overexpression of HSF1 mutants that could not bind to DNA did not restore the susceptibility to cell death in HSF1-null cells, suggesting that the new protective role of HSF1 is mediated through regulation of unknown target genes other than heat shock genes. These results uncover a novel role of vertebrate HSF1, which has been masked underthe roles of heat shock proteins.

Role of heat shock response and Hsp27 in mutant SOD1-dependent cell death

2006 ◽  
Vol 200 (2) ◽  
pp. 301-310 ◽  
Author(s):  
J. Krishnan ◽  
R. Lemmens ◽  
W. Robberecht ◽  
L. Van Den Bosch
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Mutant Sod1 ◽  
Shock Response ◽  
Dependent Cell

Identification of novel heat shock-induced long non-coding RNA in human cells

2020 ◽  
Author(s):  
Rena Onoguchi-Mizutani ◽  
Yoshihiro Kishi ◽  
Yoko Ogura ◽  
Yuuki Nishimura ◽  
Naoto Imamachi ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
A549 Cells ◽  
Heat Shock Factor 1 ◽  
Protein Coding ◽  
Heat Shock Stress ◽  
Non Coding Rna ◽  
Shock Response ◽  
Inducible Protein ◽  
Inducible Genes

Abstract The heat-shock response is a crucial system for survival of organisms under heat stress. During heat-shock stress, gene expression is globally suppressed, but expression of some genes, such as chaperone genes, is selectively promoted. These selectively activated genes have critical roles in the heat-shock response, so it is necessary to discover heat-inducible genes to reveal the overall heat-shock response picture. The expression profiling of heat-inducible protein-coding genes has been well-studied, but that of non-coding genes remains unclear in mammalian systems. Here, we used RNA-seq analysis of heat shock-treated A549 cells to identify seven novel long non-coding RNAs that responded to heat shock. We focussed on CTD-2377D24.6 RNA, which is most significantly induced by heat shock, and found that the promoter region of CTD-2377D24.6 contains the binding site for transcription factor HSF1 (heat shock factor 1), which plays a central role in the heat-shock response. We confirmed that HSF1 knockdown cancelled the induction of CTD-2377D24.6 RNA upon heat shock. These results suggest that CTD-2377D24.6 RNA is a novel heat shock-inducible transcript that is transcribed by HSF1.

scholarly journals Anticancer effects of mifepristone on human uveal melanoma cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Prisca Bustamante Alvarez ◽  
Alexander Laskaris ◽  
Alicia A. Goyeneche ◽  
Yunxi Chen ◽  
Carlos M. Telleria ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Progesterone Receptor ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Caspase 3 ◽  
Annexin V ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Free Dna

Abstract Background Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds. Methods The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 μM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR. Results MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. Conclusion This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.

Thermal acclimation changes DNA-binding activity of heat shock factor 1(HSF1) in the gobyGillichthys mirabilis: implications for plasticity in the heat-shock response in natural populations

2002 ◽  
Vol 205 (20) ◽  
pp. 3231-3240 ◽  
Author(s):  
Bradley A. Buckley ◽  
Gretchen E. Hofmann
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Environmental Control ◽  
Heat Shock Factor ◽  
Thermal Acclimation ◽  
Model Systems ◽  
Threshold Temperature ◽  
Heat Shock Factor 1 ◽  
Shock Response

SUMMARYThe intracellular build-up of thermally damaged proteins following exposure to heat stress results in the synthesis of a family of evolutionarily conserved proteins called heat shock proteins (Hsps) that act as molecular chaperones, protecting the cell against the aggregation of denatured proteins. The transcriptional regulation of heat shock genes by heat shock factor 1(HSF1) has been extensively studied in model systems, but little research has focused on the role HSF1 plays in Hsp gene expression in eurythermal organisms from broadly fluctuating thermal environments. The threshold temperature for Hsp induction in these organisms shifts with the recent thermal history of the individual but the mechanism by which this plasticity in Hsp induction temperature is achieved is unknown. We examined the effect of thermal acclimation on the heat-activation of HSF1 in the eurythermal teleost Gillichthys mirabilis. After a 5-week acclimation period (at 13, 21 or 28°C) the temperature of HSF1 activation was positively correlated with acclimation temperature. HSF1 activation peaked at 27°C in fish acclimated to 13°C, at 33°C in the 21°C group, and at 36°C in the 28°C group. Concentrations of both HSF1 and Hsp70 in the 28°C group were significantly higher than in the colder acclimated fish. Plasticity in HSF1 activation may be important to the adjustable nature of the heat shock response in eurythermal organisms and the environmental control of Hsp gene expression.

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