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 Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.

2021 ◽  
Author(s):  
Mhoriam Ahmed ◽  
Charlotte Spicer ◽  
Jasmine Harley ◽  
Nikolaj Petersen ◽  
Paul Taylor ◽  
...  
Keyword(s):  
Heat Shock ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Pathological Changes ◽  
Beneficial Effects ◽  
Disease Spectrum ◽  
Shock Response ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now widely considered to be part of a disease spectrum with the identification of common pathological features and genetic causes. However, despite these advances, there remains no effective therapy for these conditions. In this study we demonstrate that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype. Moreover, the beneficial effects of arimoclomol are seen in both fibroblasts and iPSC-derived motor neurons from patients. Importantly, we show the pathological changes targeted by arimoclomol in our experimental models are present in post-mortem FTD patient tissue. Together with previous data demonstrating the efficacy of arimoclomol in SOD1-ALS models, our findings suggest that arimoclomol may have therapeutic potential not only in non-SOD1 ALS but also for the treatment of FTD.

Histone deacetylase 6 regulates cytotoxic α-synuclein accumulation through induction of the heat shock response

2014 ◽  
Vol 35 (10) ◽  
pp. 2316-2328 ◽  
Author(s):  
Yunlan Du ◽  
Fei Wang ◽  
Jing Zou ◽  
Weidong Le ◽  
Qing Dong ◽  
...  
Keyword(s):  
Heat Shock ◽  
Histone Deacetylase ◽  
Heat Shock Response ◽  
Histone Deacetylase 6 ◽  
Shock Response

scholarly journals The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

2014 ◽  
Vol 290 (3) ◽  
pp. 1623-1638 ◽  
Author(s):  
Angela L. Davis ◽  
Shuxi Qiao ◽  
Jessica L. Lesson ◽  
Montserrat Rojo de la Vega ◽  
Sophia L. Park ◽  
...  
Keyword(s):  
Heat Shock ◽  
Malignant Melanoma ◽  
Heat Shock Response ◽  
Melanoma Cells ◽  
Quinone Methide ◽  
Proteotoxic Stress ◽  
Shock Response

Inhibition of Heat Shock Factor 1 (HSF1) Is More Effective At Sensitizing Myeloma Cells to Bortezomib Than Inhibition of Individual HSF1 Targets.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2953-2953
Author(s):  
Shardule P Shah ◽  
Sagar Lonial ◽  
Lawrence H. Boise
Keyword(s):  
Multiple Myeloma ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Conflicts Of Interest ◽  
The United States ◽  
Myeloma Cell ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Shock Response ◽  
Induced Apoptosis

Abstract Abstract 2953 Multiple myeloma is a plasma cell disorder with an average incidence of 21,000 new cases per year in the United States. Recent advances in therapeutic approaches such as the use of proteasome inhibitors have resulted in a significant increase in the overall survival of myeloma patients. Myeloma cells maintain many of the characteristics of normal plasma cells, including constitutive immunoglobulin production and secretion, therefore management of ER stress plays a role in myeloma cell sensitivity to proteasome inhibition. However, myeloma cells also upregulate protective genes in response to the proteotoxic stress that can limit the therapeutic response. Previous groups have published on the importance of the heat shock response and the heat shock protein (HSP) family, supporting preclinical and clinical exploration of HSP inhibition in myeloma. Our group had interest in regulation of the HSP response and has evaluated the master regulator HSF1 as a potential therapeutic target. We found that siRNA-mediated silencing of HSF1 enhances bortezomib-induced apoptosis in a myeloma cell line. To define the effectors of the heat shock response important in regulating bortezomib response, we determined which heat shock response genes are induced by bortezomib in an HSF1-dependent manner. From a realtime PCR array of 84 HSP family genes, we found 21 genes that were induced greater than 2-fold by bortezomib. Of these 21 genes, 10 genes showed >50% reduction in HSF1-silenced cells. 7/10 genes were confirmed by independent qRT-PCR and western blot analysis. These genes include: CRYAB (alpha-crystallin B chain), DNAJB1 (HSP40 subfamily B), HSPA1A (HSP70-1A), HSPA1B (HSP70-1B), HSPB1 (HSP27), HSPH1 (HSP105/110), and HSP90AB1 (HSP90b1). To begin to determine which of these genes was important for the HSF1-dependent protective response we silenced the 7 genes individually and subsequently treated the cells with bortezomib. Surprisingly only 1 of the 7 genes silenced individually, DNAJB1, had an observable effect on bortezomib-induced death. However DNAJB1 silencing does not account for all the HSF1 activity as the increase in cell death due to bortezomib is only 48% of that observed with HSF1 silencing. Thus targeting HSF1 is more effective at sensitizing multiple myeloma cells to bortezomib-induced apoptosis than targeting individual HSPs. Moreover these data suggest that HSP90 inhibitors are functioning by inhibiting at least two members of this family to be effective as single agents. Therefore, while clinical trials for individual HSP and HSP in combination with bortezomib are being conducted, a more effective strategy for apoptosis induction is achieved through inhibition of HSP regulators such as HSF1 in combination with bortezomib. These results provide support for investigating HSP regulation in response to PI to increase the efficacy of myeloma therapy. Disclosures: No relevant conflicts of interest to declare.

Expression of iNOS in cultured rat pulmonary artery smooth muscle cells is inhibited by the heat shock response

1995 ◽  
Vol 269 (6) ◽  
pp. L843-L848 ◽  
Author(s):  
H. R. Wong ◽  
J. D. Finder ◽  
K. Wasserloos ◽  
B. R. Pitt
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Sodium Arsenite ◽  
Dependent Manner ◽  
Inos Gene ◽  
Shock Response ◽  
Pulmonary Artery Smooth Muscle ◽  
Inos Gene Expression

The heat shock response is a highly conserved stress response known to alter patterns of gene expression in many cell types. We hypothesized that interleukin-1 beta (IL-1 beta)-mediated inducible nitric oxide synthase (iNOS) gene expression would be inhibited after induction of the heat shock response in cultured rat pulmonary artery smooth muscle cells (RPASMC). Exposure of RPASMC to sodium arsenite or heat led to expression of heat shock protein-70 (HSP-70) in a time- and concentration-dependent manner. Prior induction of the heat shock response inhibited IL-1 beta-mediated iNOS gene expression in a time- and dose-dependent manner. The inhibitory effects were not due to cytotoxicity, since cell viability was not affected by either sodium arsenite, heat, IL-1 beta, or their combination. Transcriptional analysis via transient transfection of the murine macrophage iNOS promoter [-1592 and -367 base pairs (bp)], upstream from the reporter gene luciferase, revealed that the heat shock response did not affect IL-1 beta-mediated promoter activation, as measured by luciferase activity. We conclude that induction of the heat shock response inhibits IL-1 beta-mediated iNOS gene expression in cultured RPASMC.

scholarly journals Proteotoxic stress of cancer: Implication of the heat-shock response in oncogenesis

2012 ◽  
Vol 227 (8) ◽  
pp. 2982-2987 ◽  
Author(s):  
Chengkai Dai ◽  
Siyuan Dai ◽  
Junyue Cao
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Proteotoxic Stress ◽  
Shock Response

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.

Sign in / Sign up

Export Citation Format

Share Document