scholarly journals HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection

2020 ◽  
Vol 6 (46) ◽  
pp. eabc6871
Author(s):  
Zijian Tang ◽  
Kuo-Hui Su ◽  
Meng Xu ◽  
Chengkai Dai
Keyword(s):  
Neurodegenerative Disorders ◽  
Heat Shock Factor 1 ◽  
Phosphatidylinositol 3 Kinase ◽  
Mitochondrial Proteome ◽  
Proteotoxic Stress ◽  
Amyloid Oligomers ◽  
Tumor Suppressive Function ◽  
Overgrowth Syndromes

The role of proteomic instability in cancer, particularly amyloidogenesis, remains obscure. Heat shock factor 1 (HSF1) transcriptionally governs the proteotoxic stress response to suppress proteomic instability and enhance survival. Paradoxically, HSF1 promotes oncogenesis. Here, we report that AKT activates HSF1 via Ser230 phosphorylation. In vivo, HSF1 enables megalencephaly and hepatomegaly, which are driven by hyperactive phosphatidylinositol 3-kinase/AKT signaling. Hsf1 deficiency exacerbates amyloidogenesis and elicits apoptosis, thereby countering tissue overgrowth. Unexpectedly, HSF1 physically neutralizes soluble amyloid oligomers (AOs). Beyond impeding amyloidogenesis, HSF1 shields HSP60 from direct assault by AOs, averting HSP60 destabilization, collapse of the mitochondrial proteome, and, ultimately, mitophagy and apoptosis. The very same mechanism occurs in Alzheimer’s disease. These findings suggest that amyloidogenesis may be a checkpoint mechanism that constrains uncontrolled growth and safeguards tissue homeostasis, congruent with its emerging tumor-suppressive function. HSF1, by acting as an anti-amyloid factor, promotes overgrowth syndromes and cancer but may suppress neurodegenerative disorders.

scholarly journals HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1363 ◽  
Author(s):  
Hyeji Kang ◽  
Taerim Oh ◽  
Young Yil Bahk ◽  
Geon-Hee Kim ◽  
Sang-Yeon Kan ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Metabolic Stress ◽  
Mapk Signaling ◽  
Heat Shock Factor 1 ◽  
Antiproliferative Effects ◽  
Proteotoxic Stress ◽  
Cholesterol Biosynthesis Pathway ◽  
Increased Activity ◽  
Essential Transcription Factor

Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.

scholarly journals Emerging roles of DYRK2 in cancer

2020 ◽  
pp. jbc.REV120.015217
Author(s):  
Vasudha Tandon ◽  
Laureano de la Vega ◽  
Sourav Banerjee
Keyword(s):  
Tumour Suppressor ◽  
26S Proteasome ◽  
Heat Shock Factor 1 ◽  
Lung Cancers ◽  
Nuclear Stability ◽  
Spatio Temporal ◽  
Temporal Interactions

Over the last decade, the CMGC-kinase, DYRK2, has been reported as a tumour-suppressor across various cancers triggering major anti-tumour and pro-apoptotic signals in breast, colon, liver, ovary, brain, and lung cancers, while lower DYRK2 expression apparently correlated with poorer prognosis in patients. Contrary to this, various medicinal chemistry studies reported robust anti-proliferative properties of DYRK2 inhibitors while unbiased ‘omics’ and GWAS based studies identified DYRK2 as a highly overexpressed kinase in various patient tumour samples. A major paradigm shift occurred in the last four years when DYRK2 was found to regulate proteostasis in cancer via a two-pronged mechanism. DYRK2 phosphorylated and activated the 26S proteasome to enhance degradation of mis-folded/tumour-suppressor proteins while also promoting the nuclear stability and transcriptional activity of its substrate, heat-shock factor 1 (HSF1) triggering protein folding. Together, DYRK2 regulates proteostasis and promotes pro-tumorigenic survival for specific cancers. Indeed, potent and selective small molecule inhibitors of DYRK2 exhibit in vitro and in vivo anti-tumour activity in triple negative breast cancer (TNBC) and myeloma models. Thus, with conflicting and contradictory reports across different cancers, the overarching role of DYRK2 remains enigmatic. Specific cancer (sub)types coupled to spatio-temporal interactions with substrates could decide the pro- or anti-cancer role of DYRK2. The current review aims to provide a balanced and critical appreciation of the literature-to-date highlighting top substrates such as p53, c-Myc, c-Jun, HSF1, proteasome or NOTCH1, to discuss DYRK2 inhibitors available to the scientific community, and to shed light on this duality of pro- and anti-tumorigenic roles of DYRK2.

scholarly journals HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

2017 ◽  
Author(s):  
Toshiki Kijima ◽  
Thomas L. Prince ◽  
Megan L. Tigue ◽  
Kendrick H. Yim ◽  
Harvey Schwartz ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transcriptional Activity ◽  
Transcriptional Response ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor 1 ◽  
Hsp90 Inhibitors ◽  
Dynamic Modulation ◽  
Proteotoxic Stress ◽  
Significant Prolongation

AbstractHeat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

scholarly journals Tau Accumulation via Reduced BAG3-mediated Autophagy Is Required for GGGGCC Repeat Expansion-Induced Neurodegeneration

2019 ◽  
Author(s):  
Xue Wen ◽  
Ping An ◽  
Hexuan Li ◽  
Zijian Zhou ◽  
Yimin Sun ◽  
...  
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Motor Performance ◽  
Molecular Mechanisms ◽  
Repeat Expansion ◽  
Cag Repeats ◽  
Reduced Activity ◽  
Lateral Sclerosis

SUMMARYExpansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats (CAGr) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r. Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r-induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.

scholarly journals Tissue- and stimulus-dependent role of phosphatidylinositol 3-kinase isoforms for neutrophil recruitment induced by chemoattractants in vivo

2008 ◽  
Vol 180 (11) ◽  
pp. 7775.1-7775
Author(s):  
V. Pinho ◽  
R. de Castro Russo ◽  
F. A. Amaral ◽  
L. P. de Sousa ◽  
M. M. Barsante ◽  
...  
Keyword(s):  
Neutrophil Recruitment ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3-Kinase Isoforms for Neutrophil Recruitment Induced by Chemoattractants In Vivo

2007 ◽  
Vol 179 (11) ◽  
pp. 7891-7898 ◽  
Author(s):  
Vanessa Pinho ◽  
Remo de Castro Russo ◽  
Flávio A. Amaral ◽  
Lirlândia P. de Sousa ◽  
Michele M. Barsante ◽  
...  
Keyword(s):  
Neutrophil Recruitment ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

CAL-101, a Selective Inhibitor of the p110δ Isoform of Phosphatidylinositol 3-Kinase, Effectively Induces Apoptosis in Primary Chronic Lymphocytic Leukemia Cells Providing a Novel Therapeutic Strategy for the Treatment of This Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3165-3165 ◽  
Author(s):  
Sarah E. May ◽  
Adam Kashishian ◽  
Thomas S. Lin ◽  
Jeffrey A. Jones ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
B Cell ◽  
Nk Cells ◽  
Phase 1 ◽  
Phosphatidylinositol 3 Kinase ◽  
Phase 1 Clinical Trial

Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a pivotal role in cell proliferation and survival that underlies the biology of many cancers including CLL. Of the eight distinct mammalian isoforms of PI3K, it is the class IA PI3Ks (p110α, p110β and p110δ) that are responsible for Akt activation and cellular transformation. The p110α and p110β isoforms both have a ubiquitous tissue distribution in adults, whereas p110δ expression is restricted to cells of hematopoietic origin. Recent studies have established a dominant role of p110δ isoform in B-cell responses. Deletion or inactivation of p110δ ablates B-cell antigen receptor (BCR)-induced phosphorylation of Akt and impairs cell cycle progression. Furthermore, CD40-ligand (CD40L) dependent survival is compromised in the absence of p110δ activity. Considering the role of p110δ-mediated BCR and CD40L-CD40 signaling to the enhanced survival in normal B cells, we hypothesized that inhibition of this kinase will induce cytotoxicity in B-CLL cells. We first examined the protein expression of p110δ in primary tumor CD19+ B cells from CLL patients and show that 24/24 CLL consistently overexpressed p110δ. The expression levels of p110α and p110β however, varied more widely, and were often undetectable. Treatment of primary tumor cells with CAL-101, a novel selective p110δ inhibitor, at concentrations of 0.1–10μM resulted in significant cell killing (linear mixed model; p=0.0004). As an example, 5μM CAL-101 resulted in a median of 59.6% viable cells (n=18 CLL patient samples). CAL-101 induced cytotoxicity was accompanied by PARP and caspase 3 cleavage. Previous published studies have demonstrated that CD40L-CD40 signaling promotes activation of CLL cells (as measured by up-regulation of CD40 and CD86) and also protection from spontaneous apoptosis ex vivo. Treatment of CLL cells in the presence of CAL-101 diminished the activation markers CD40 and CD86 induced by CD40L. In addition, an increase in CLL cell viability induced by CD40L was reversed by CAL-101 treatment. Contrasting with this, diminishment of apoptosis with IL-4 was not observed. Given the common finding of innate and cellular immune effects induced by therapies utilized in CLL, we next assessed the effect of CAL-101 on normal NK cells and T cells. Treatment of NK cells and T cells in vitro from healthy volunteers had no effect on cell viability. The lack of cytotoxic effect on normal NK cells and T cells was also assessed in vivo from a completed phase I trial of healthy volunteers that serves as a forerunner to the phase 1 clinical trial in CLL and related lymphoproliferative diseases currently ongoing. Here, treatment of normal human volunteers with CAL-101 for seven days achieved peak plasma concentrations up to 5μM without changes in general hematology or subpopulations of NK cells and T cells. Overall, our results identify the p110δ isoform as a potential therapeutic target in CLL where selective cytotoxicity is observed as compared to normal immune effector cells and the very important CD40-CD40L survival pathway is disrupted. Together, these in vitro and in vivo data provide sound validation for the ongoing Phase 1 clinical trial for the treatment of patients with CLL and related lymphoid malignancies.

scholarly journals Role of heparanase 2 (Hpa2) in gastric cancer

2021 ◽  
Author(s):  
JingJing Liu ◽  
Ibrahim Knani ◽  
Miriam Gross-Cohen ◽  
Hu Jiaxi ◽  
Wang Sumin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Carcinoma Cells ◽  
Proteotoxic Stress ◽  
Patient’S Outcome ◽  
Gastric Cancer Patients ◽  
Amp Activated Protein Kinase ◽  
Striking Contrast

Abstract BackgroundHeparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate (HS) and, consequently, remodel the extracellular matrix (ECM) underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks HS-degrading activity typical of heparanase. MethodsWe combined clinical, in vivo and in vitro studies to reveal the role of Hpa2 in gastric cancer. ResultsHere, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network known to attenuate the growth of various types of cancer including gastric cancer. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. ConclusionsThese results indicate that high levels of Hpa2 in some tumors but not in others are due to stress conditions that tumors often experience due to their high rates of cell proliferating, high metabolic demands, and changes in the tumor microenvironment. This increase in Hpa2 levels by the stressed tumors appears critically important for the patient's outcome.

scholarly journals The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160525 ◽  
Author(s):  
Chengkai Dai
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Misfolding ◽  
Heat Shock Factor 1 ◽  
Growth And Survival ◽  
Proteotoxic Stress ◽  
Shock Proteins ◽  
Misfolding Diseases

The heat-shock, or HSF1-mediated proteotoxic stress, response (HSR/HPSR) is characterized by induction of heat-shock proteins (HSPs). As molecular chaperones, HSPs facilitate the folding, assembly, transportation and degradation of other proteins. In mammals, heat shock factor 1 (HSF1) is the master regulator of this ancient transcriptional programme. Upon proteotoxic insults, the HSR/HPSR is essential to proteome homeostasis, or proteostasis, thereby resisting stress and antagonizing protein misfolding diseases and ageing. Contrasting with these benefits, an unexpected pro-oncogenic role of the HSR/HPSR is unfolding. Whereas HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival. Highlighting the HSR/HPSR as an integral component of the oncogenic network, several key pathways governing HSF1 activation by environmental stressors are causally implicated in malignancy. Importantly, HSF1 impacts the cancer proteome systemically. By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy. This review provides an overview of the role of HSF1 in oncogenesis, mechanisms underlying its constitutive activation within cancer cells and its pro-oncogenic action, as well as potential HSF1-targeting strategies. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

Mitochondrial matrix calcium ions regulate energy production in myocardium: A cytochemical study

1990 ◽  
Vol 48 (2) ◽  
pp. 166-167
Author(s):  
W.A. Jacob ◽  
R. Hertsens ◽  
A. Van Bogaert ◽  
M. De Smet
Keyword(s):  
Energy Metabolism ◽  
Calcium Ions ◽  
Energy Production ◽  
Regulation Of Respiration ◽  
Free Calcium ◽  
Mitochondrial Matrix ◽  
Cytochemical Study ◽  
Nmr Techniques

In the past most studies of the control of energy metabolism focus on the role of the phosphorylation potential ATP/ADP.Pi on the regulation of respiration. Studies using NMR techniques have demonstrated that the concentrations of these compounds for oxidation phosphorylation do not change appreciably throughout the cardiac cycle and during increases in cardiac work. Hence regulation of energy production by calcium ions, present in the mitochondrial matrix, has been the object of a number of recent studies.Three exclusively intramitochondnal dehydrogenases are key enzymes for the regulation of oxidative metabolism. They are activated by calcium ions in the low micromolar range. Since, however, earlier estimates of the intramitochondnal calcium, based on equilibrium thermodynamic considerations, were in the millimolar range, a physiological correlation was not evident. The introduction of calcium-sensitive probes fura-2 and indo-1 made monitoring of free calcium during changing energy metabolism possible. These studies were performed on isolated mitochondria and extrapolation to the in vivo situation is more or less speculative.

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