scholarly journals Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2

2021 ◽  
Author(s):  
Linda Pesonen ◽  
Sally Svartsjö ◽  
Viktor Bäck ◽  
Aurélie de Thonel ◽  
Valérie Mezger ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Heat Shock Response ◽  
Critical Role ◽  
Cell Types ◽  
Hsp90 Inhibitor ◽  
Gambogic Acid ◽  
Heat Shock Factor 1 ◽  
Dependent Manner ◽  
Shock Response

AbstractCancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) or HSF2 knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90-mutants that can be co-precipitated with HSF1, a known facilitator of cancer, we show that also endogenous HSF2 binds to the HSP90-HSF1 complex. GB and GBA treatment disrupt the interaction between HSP90 and HSF1 and HSF2. Our study implies that these compounds should be used cautiously if developed for cancer therapies, since GB and its derivative GBA are strong inducers of the HSR, in multiple cell types, by involving the dissociation of a HSP90-HSF1-HSF2 complex.

scholarly journals Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2

2021 ◽  
Author(s):  
Linda Pesonen ◽  
Sally Svartsjö ◽  
Viktor Bäck ◽  
Aurélie de Thonel ◽  
Valérie Mezger ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Heat Shock Response ◽  
Critical Role ◽  
Cell Types ◽  
Hsp90 Inhibitor ◽  
Gambogic Acid ◽  
Heat Shock Factor 1 ◽  
Dependent Manner ◽  
Shock Response

AbstractCancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity, and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) or HSF2 knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90 mutants that can be co-precipitated with HSF1, a known facilitator of cancer, we show that also endogenous HSF2 co-precipitates with HSP90. GB and GBA treatment disrupt the interaction between HSP90 and HSF1 and HSP90 and HSF2. Our study implies that these compounds should be used cautiously if developed for cancer therapies, since GB and its derivative GBA are strong inducers of the HSR, in multiple cell types, by involving the dissociation of a HSP90-HSF1/HSF2 complex.

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.

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.

Induction of the heat shock response in Arabidopsis by heat shock protein 70 inhibitor VER-155008

2019 ◽  
Vol 46 (10) ◽  
pp. 925
Author(s):  
Erina Matsuoka ◽  
Naoki Kato ◽  
Masakazu Hara
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Response ◽  
Wheat Germ ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Wheat Germ Extract ◽  
Chlorophyll Contents ◽  
Shock Response ◽  
Human Hsp70

The heat shock protein 90 (HSP90) inhibitor, geldanamycin, is a chemical inducer of the heat shock response (HSR) in Arabidopsis. Geldanamycin is thought to activate the heat shock signal by dissociating the HSP90-heat shock factor (HSF) complex. Recent studies have indicated that plant HSP70 is also associated with HSF, suggesting that inhibition of HSP70 may induce the HSR. However, no studies have been conducted to test this hypothesis. Here, we found that a specific HSP70 inhibitor VER-155008 activated the promoter of a small HSP gene (At1 g53540, HSP17.6C-CI) of Arabidopsis, which was shown to be activated by geldanamycin and other HSP90 inhibitors. The production of HSP17.6C-CI, HSP70 and HSP90.1 proteins in Arabidopsis was enhanced by the addition of VER-155008. The reduction of chlorophyll contents by heat shock was ameliorated by VER-155008. Chaperone analyses indicated that VER-155008 inhibited the chaperone activities of wheat germ extract and human HSP70/HSP40, respectively. These results suggest that the inhibition of HSP70 by VER-155008 enhanced the heat tolerance of Arabidopsis by inducing the HSR in the plant.

During ischemia-reperfusion in rat kidneys, heat shock response is not regulated by expressional changes of heat shock factor 1

2000 ◽  
Vol 13 (4) ◽  
pp. 297-302 ◽  
Author(s):  
Ziya Akçetin ◽  
Reinhard Pregla ◽  
Dorothea Darmer ◽  
Hans-Jürgen Brömme ◽  
Jürgen Holtz
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Ischemia Reperfusion ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Rat Kidneys

scholarly journals Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

2020 ◽  
Vol 25 (1) ◽  
pp. 173-191 ◽  
Author(s):  
Rachel Kuta ◽  
Nancy Larochelle ◽  
Mario Fernandez ◽  
Arun Pal ◽  
Sandra Minotti ◽  
...  
Keyword(s):  
Heat Shock ◽  
Histone Deacetylase ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Stress Dependent

AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

scholarly journals Targeting Heat Shock Response to Sensitize Cancer Cells to Proteasome and Hsp90 Inhibitors

2006 ◽  
Vol 66 (3) ◽  
pp. 1783-1791 ◽  
Author(s):  
Nava Zaarur ◽  
Vladimir L. Gabai ◽  
John A. Porco ◽  
Stuart Calderwood ◽  
Michael Y. Sherman
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Heat Shock Response ◽  
Hsp90 Inhibitors ◽  
Shock Response

A new HSP90 inhibitor as therapeutic agent for bladder cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 416-416
Author(s):  
Weiya Liu ◽  
Eugene K. Lee ◽  
Karim Pirani ◽  
Brian S. J. Blagg ◽  
Jeffrey M. Holzbeierlein
Keyword(s):  
Bladder Cancer ◽  
Heat Shock ◽  
Western Blot ◽  
Protein Degradation ◽  
Cancer Cells ◽  
Hsp90 Inhibitor ◽  
Client Protein ◽  
Antiproliferative Effects ◽  
Bladder Cancer Cells ◽  
Shock Response

416 Background: Hsp90 represents one of the most promising biological targets for the treatment of cancer, including bladder cancer. A number of Hsp90 inhibitors that target the N-terminal ATP-binding pocket have demonstrated potent antiproliferative effects. However, a major drawback is that they induce a prosurvival heat shock response (HSR). We demonstrate the effects of a novel Hsp90 beta selective inhibitor on bladder cancer cells, which shows potent antiproliferative effects without inducing HSR. Methods: Cell Titer-Glo luminescent anti-proliferative assay was used to determine the IC50 numbers in UC3 cells. Trypan Blue Cytotoxicity assay was performed for 24h treatment with increasing concentrations of the inhibitor. Effects of the cmpound on Hsp90’s client protein degradation were investigated by Western Blot. Results: This new compound exhibits potent anti-proliferative in bladder cancer cells. IC50 number is determined as 0.30 µM for UC3 cancer cells. The toxicity assay was also performed over UC3 cells at 24h.1uM KU new compound has the similar effects on UC3 cells as 10 uM 17AAG: inhibit the cancer cells growth to half, but maintain over 60% viability of the cells. The western blot were also performed over UC3 cells, and some new target proteins such as FGFR3 and PKM2 were investigated. The data showed that, this new compound would not induce the heat shock response like 17AAG (Hsp27), and did cause some Hsp90β related protein degradation (CXCR4). FGFR3, PKM2, Her2, Hsf-1and B-raf all show degradation to different extent. Conclusions: A novel Hsp90 inhibitor, exhibits potent anti-proliferative and cytotoxic activity along with client protein degradation, without induction of HSR in bladder cancer cell lines. The reduction of Hsp90 beta related client protein caused by this compound suggests the potential to develop isoform specific inhibitors of Hsp90 for better antitumor therapies.

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