scholarly journals Identification of Inhibitors of HSF1 Functional Activity by High-Content Target-Based Screening

2009 ◽  
Vol 14 (10) ◽  
pp. 1165-1175 ◽  
Author(s):  
Qingyan Au ◽  
Yingjia Zhang ◽  
Jack R. Barber ◽  
Shi Chung Ng ◽  
Bin Zhang
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Small Molecule ◽  
Hela Cells ◽  
Significant Inhibition ◽  
Cancer Drug ◽  
Heat Shock Factor 1 ◽  
Mobility Shift ◽  
Granule Formation ◽  
High Level

Cancer cells are known to experience a high level of stress and may require constant repair for survival and proliferation. Recent studies showed that inhibition of heat shock factor 1 (HSF1), the key regulator for the stress-activated transcription of heat shock protein (HSP), can reduce the tumorigenic potential of cancer cells. Such a “nononcogene addiction” phenomenon makes HSF1 an attractive cancer drug target. Here, the authors report an image-based high-content screening (HCS) assay for HSF1 functional inhibitors. A heat shock—based methodology was used to stimulate the stress response followed by quantitative measurement of HSF1/HSP70 granules for compound-induced inhibitory effects. The authors discovered a small molecule from a compound library that inhibits HSF1 granule formation substantially in heat-shocked HeLa cells with IC50 at 80 nM. Electorphoretic mobility shift of HSF1 by this compound suggested significant inhibition of HSF1 phosphorylation, accompanied by reduced expression levels of HSP70 and HSP90 after heat induction. Importantly, HeLa cells stably transfected with HSF1 shRNA were more resistant to the compound treatment under lethal temperature than cells containing HSF1, further validating an HSF1-dependent mechanism of action. The HCS assay the authors developed was robust with a Z′ factor of 0.65 in a 384-well plate format, providing a valuable method for identifying small-molecule functional inhibitors of HSF1 for potential cancer treatment. ( Journal of Biomolecular Screening 2009:1165-1175)

scholarly journals Human Chromosomes 9, 12, and 15 Contain the Nucleation Sites of Stress-Induced Nuclear Bodies

2002 ◽  
Vol 13 (6) ◽  
pp. 2069-2079 ◽  
Author(s):  
Marco Denegri ◽  
Daniela Moralli ◽  
Mariano Rocchi ◽  
Marco Biggiogera ◽  
Elena Raimondi ◽  
...  
Keyword(s):  
Heat Shock ◽  
Human Cell ◽  
Hela Cells ◽  
Heat Shock Factor ◽  
Nuclear Bodies ◽  
Chromosome 9 ◽  
Heat Shock Factor 1 ◽  
Human Chromosomes ◽  
Cell Hybrids ◽  
Nucleation Sites

We previously reported the identification of a novel nuclear compartment detectable in heat-shocked HeLa cells that we termed stress-induced Src-activated during mitosis nuclear body (SNB). This structure is the recruitment center for heat shock factor 1 and for a number of RNA processing factors, among a subset of Serine-Arginine splicing factors. In this article, we show that stress-induced SNBs are detectable in human but not in hamster cells. By means of hamster>human cell hybrids, we have identified three human chromosomes (9, 12, and 15) that are individually able to direct the formation of stress bodies in hamster cells. Similarly to stress-induced SNB, these bodies are sites of accumulation of hnRNP A1-interacting protein and heat shock factor 1, are usually associated to nucleoli, and consist of clusters of perichromatin granules. We show that the p13-q13 region of human chromosome 9 is sufficient to direct the formation of stress bodies in hamster>human cell hybrids. Fluorescence in situ hybridization experiments demonstrate that the pericentromeric heterochromatic q12 band of chromosome 9 and the centromeric regions of chromosomes 12 and 15 colocalize with stress-induced SNBs in human cells. Our data indicate that human chromosomes 9, 12, and 15 contain the nucleation sites of stress bodies in heat-shocked HeLa cells.

scholarly journals Inhibiting Heat Shock Factor 1 in Human Cancer Cells with a Potent RNA Aptamer

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96330 ◽  
Author(s):  
H. Hans Salamanca ◽  
Marc A. Antonyak ◽  
Richard A. Cerione ◽  
Hua Shi ◽  
John T. Lis
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Human Cancer ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Rna Aptamer ◽  
Human Cancer Cells

Skeletal muscles of aged male mice fail to adapt following contractile activity

2003 ◽  
Vol 31 (2) ◽  
pp. 455-456 ◽  
Author(s):  
A. Vasilaki ◽  
L.M Iwanejko ◽  
F. McArdle ◽  
C.S. Broome ◽  
M.J. Jackson ◽  
...  
Keyword(s):  
Heat Shock ◽  
Contractile Activity ◽  
Northern Blotting ◽  
Heat Shock Factor 1 ◽  
Mrna Levels ◽  
Mobility Shift ◽  
Aged Mice ◽  
Adult Mice ◽  
Hind Limbs ◽  
Mobility Shift Assay

Skeletal muscle adapts rapidly following exercise by the increased production of heat-shock proteins (HSPs). The aim of this study was to examine the ability of muscle from adult and aged mice to produce HSPs following non-damaging exercise. Adult and aged B6XSJL mice were anaesthetized and their hind limbs were subjected to isometric contractions. At different time points, muscles were analysed for HSP production by Western and Northern blotting and by electrophoretic mobility-shift assay. HSP protein and mRNA levels in muscles from adult mice increased significantly following exercise. This was not evident in muscles of aged mice. In contrast, binding of the transcription factor heat-shock factor 1 (HSF1) was not grossly altered in muscles of aged mice compared with adult mice. The data suggest that the inability of muscles of aged mice to produce HSPs appears to be due to alterations during gene transcription.

scholarly journals Heat shock factor 1 confers resistance to lapatinib in ERBB2-positive breast cancer cells

2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Alisha Yallowitz ◽  
Amr Ghaleb ◽  
Lucas Garcia ◽  
Evguenia M. Alexandrova ◽  
Natalia Marchenko
Keyword(s):  
Breast Cancer ◽  
Heat Shock ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Positive Breast Cancer

scholarly journals Identification of a mitochondria-targeting fluorescent small molecule for dual phototherapy

2018 ◽  
Vol 11 (04) ◽  
pp. 1850016 ◽  
Author(s):  
Jie Chen ◽  
Xu Tan ◽  
Shenglin Luo ◽  
Lei Long ◽  
Lang Liu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Near Infrared ◽  
Significant Inhibition ◽  
Cytotoxicity Studies ◽  
Inhibition Of Tumor Growth ◽  
High Cytotoxicity ◽  
Mitochondria Targeting

Phototherapy, mainly including photodynamic therapy (PDT) and photothermal therapy (PTT), is a noninvasive and effective approach for cancer treatment. Since integration of PDT and PTT for simultaneous synergistic PDT/PTT treatment enables us to improve phototherapeutic efficacy significantly, it has been attracting a lot of investigations in current days. Here, we introduce IR-52, a new mitochondria-targeting near infrared (NIR) fluorescent small molecule, which possesses structure-inherent PTT and PDT synergistic phototherapeutic effects without conjugation to specific ligands. After NIR light irradiation (808[Formula: see text]nm, 2[Formula: see text]W/cm2, 5[Formula: see text]min), both the hyperthermia and excessive singlet oxygen levels were determined when dissolving IR-52 in aqueous solutions. In vitro photoinduced cytotoxicity studies showed significant lower cell viabilities and higher necrotic/apoptotic rates when cancer cells were treated with IR-52 and irradiation, and its’ mitochondrial localization in cancer cells would partially explain its high cytotoxicity. Further in vivo synergetic PDT and PTT effects were demonstrated by high tumor surface temperature and significant inhibition of tumor growth. Our results strongly suggest that IR-52, which possesses excellent photosensitivity, may provide a promising strategy for tumor treatment with decreased side effects.

scholarly journals Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1418
Author(s):  
Damian Robert Sojka ◽  
Sylwia Hasterok ◽  
Natalia Vydra ◽  
Agnieszka Toma-Jonik ◽  
Anna Wieczorek ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Protein A ◽  
Heat Shock Factor 1 ◽  
Mcf7 Cells ◽  
In Vivo Models ◽  
Genetic Ablation ◽  
Anticancer Effects

Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments.

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