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Patrick Antonietti, Benedikt Linder, Stephanie Hehlgans, Iris C Mildenberger, Michael C Burger, Simone Fulda, Joachim P Steinbach, Florian Gessler, Franz Rodel, Michel Mittelbronn, Donat Kogel
Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 (heat shock factor 1) acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, while these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels...
October 24, 2016: Molecular Cancer Therapeutics
Ting-Yu Wang, Young-Mao Chen, Tzong-Yueh Chen
Heat shock transcription factor 1 (HSF1) regulates heat shock proteins (HSPs), which assist in protein folding and inhibit protein denaturation following stress. HSF1 was firstly cloned from orange-spotted grouper and exists as two isoforms, one with (osgHSF1a) and one without (osgHSF1b) exon 11. Heat exposure increased the expression of osgHSF1b while cold exposure increased that of osgHSF1a. Both isoforms were mainly expressed in the brains, eyes, and fins. Expression of osgHSF1b was higher than osgHSF1a during development...
October 20, 2016: Fish & Shellfish Immunology
Denghe Liu, Lu Sun, Xue Qin, Tianhua Liu, Shu Zhang, Yinkun Liu, Shan Li, Kun Guo
OBJECTIVE: Reprogramming energy metabolism has been defined as the ninth hallmark of cancer; glucose deprivation might be a novel, feasible and effective approach for cancer treatment. However, the comprehensive illustration of behavior alteration of hepatocellular carcinoma (HCC) cells induced by glucose restriction is lacking and associated molecular mechanism is still unclear. METHODS: Three human HCC cell lines were cultured with normal control (25.0 mM D-glucose) and low glucose (5...
September 2016: Discovery Medicine
Carl S Rye, Nicola E A Chessum, Scott Lamont, Kurt G Pike, Paul Faulder, Julie Demeritt, Paul Kemmitt, Julie Tucker, Lorenzo Zani, Matthew D Cheeseman, Rosie Isaac, Louise Goodwin, Joanna Boros, Florence Raynaud, Angela Hayes, Alan T Henley, Emmanuel de Billy, Christopher J Lynch, Swee Y Sharp, Robert Te Poele, Lisa O' Fee, Kevin M Foote, Stephen Green, Paul Workman, Keith Jones
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay...
August 1, 2016: MedChemComm
Satoshi Ogasawara, Kouhei Hashizume, Takashi Okuno, Toshiyasu Imaizumi, Yui Inomata, Yu Tezuka, Atushi Sanbe, Daijiro Kurosaka
PURPOSE: We investigated whether heat-shock transcription factor 1 (HSF1) was involved in ultraviolet radiation type B (UVR-B)-induced lens opacity (cataract) using HSF1 heterozygous mice. We also examined the effects of geranylgeranylacetone (GGA), an inducer of heat-shock proteins via activation of HSF, on the UVR-B-induced cataract. MATERIAL AND METHODS: Male HSF1(+/-) and WT mice were unilaterally exposed to UVR-B (total: 1200mJ) at 16 weeks of age. At 48 h after the last UVR-B irradiation, the lens was isolated and the induction of the cataract was quantified as the cataract area ratio (opacity area/anterior capsule)...
October 12, 2016: Current Eye Research
Yesim Gökmen-Polar, Sunil Badve
Heat shock transcription factor 1 (HSF1), a key regulator of the heat-shock response, is deregulated in many cancers. HSF1 can mediate cancer cell survival and metastasis. High levels of HSF1 have been associated with poor prognosis in breast cancer. The nature of HSF1 upregulation needs to be validated in different cohorts to further validate its prognostic utility in breast cancer.We first evaluated its expression in a cohort of breast cancer tissue microarrays with Oncotype DX recurrence scores available using immunohistochemistry...
October 4, 2016: Oncotarget
Peizhao Du, Fangjie Dai, Yaowei Chang, Chunyan Wei, Jing Yan, Jiming Li, Xuebo Liu
Our study explored effects of miR-199b-5p on angiogenesis in mouse myocardial microvascular endothelial cells (MMVECs) and the involved working mechanisms. We applied explant culture to incubate C57/BL6 mouse MMVECs. Lipofection was used to transfect miR-199b-5p mimic, miR-199b-5p inhibitor and miR-199b-5p scramble respectively. MMVECs were divided into miR-199b-5p up-regulation, miR-199b-5p down-regulation and control groups based on above sequence. Expressions of miR-199b-5p, heat shock factor protein 1 (HSF1) mRNA were assessed by real-time quantitative polymerase chain reaction (RT-QPCR)...
September 14, 2016: Environmental Toxicology and Pharmacology
N V Maluchenko, H W Chang, M T Kozinova, M E Valieva, N S Gerasimova, A V Kitashov, M P Kirpichnikov, P G Georgiev, V M Studitsky
Conventional antitumor therapy is often complicated by the emergence of the so-called cancer stem cells (CSCs), which are characterized by low metabolic rates and high resistance to almost all existing therapies. Many problems of clinical oncology and a poor efficacy of current treatments in particular are ascribed to CSCs. Therefore, it is important to develop new compounds capable of eliminating both rapidly proliferating tumor cells and standard treatment-resistant CSCs. Curaxins have been demonstrated to manifest various types of antitumor activity...
July 2016: Molekuliarnaia Biologiia
Hye Yun Kim, Yong-Sam Kim, Hye Hyeon Yun, Chang-Nim Im, Jeong-Heon Ko, Jeong-Hwa Lee
B-cell lymphoma (BCL)-2-interacting cell death suppressor (BIS) has diverse cellular functions depending on its binding partners. However, little is known about the effects of biochemical modification of BIS on its various activities under oxidative stress conditions. In this study, we showed that H2O2 reduced BIS mobility on SDS-polyacrylamide gels in a time-dependent manner via the activation of extracellular signaling-regulated kinase (ERK). The combined results of mass spectroscopy and computational prediction identified Thr285 and Ser289 in BIS as candidate residues for phosphorylation by ERK under oxidative stress conditions...
September 23, 2016: Experimental & Molecular Medicine
Erlinda The, Peizhao Du, Yaowei Chang, Fangjie Dai, Chunyan Wei, Jiming Li
PURPOSE: Our previous studies discovered that Heat shock factor 1(HSF1) can alleviate pressure overload induced heart failure in mice. However, its molecular mechanisms are yet to be further explained. Many studies have already verified that Adenylyl Cyclase 6 (AC6) can ameliorate heart failure, but it is still unknown whether or not the pathway HSF1 is involved in the process. Our preliminary experiment showed that the expression level of AC6 is positively associated with HSF1. Therefore, in the present study, we aimed to explore whether HSF1 can play its role in ameliorating heart failure by regulating AC6, and how the potential internal mechanisms work...
August 22, 2016: Environmental Toxicology and Pharmacology
Sara Ortega-Atienza, Blazej Rubis, Caitlin McCarthy, Anatoly Zhitkovich
Endogenous and exogenous formaldehyde (FA) has been linked to cancer, neurotoxicity, and other pathophysiologic effects. Molecular and cellular mechanisms that underlie FA-induced damage are poorly understood. In this study, we investigated whether proteotoxicity is an important, unrecognized factor in cell injury caused by FA. We found that irrespective of their cell cycle phases, all FA-treated human cells rapidly accumulated large amounts of proteins with proteasome-targeting K48-linked polyubiquitin, which was comparable with levels of polyubiquitination in proteasome-inhibited MG132 controls...
September 14, 2016: American Journal of Pathology
Rachel Greenberg Scheraga, Christopher Thompson, Mohan E Tulapurkar, Ashish C Nagarsekar, Mark Cowan, Ratnakar Potla, Junfeng Sun, Rongman Cai, Carolea Logun, James Shelhamer, Nevins W Todd, Ishwar S Singh, Irina G Luzina, Sergei P Atamas, Jeffrey D Hasday
We previously showed that coincident exposure to heat shock (HS; 42°C for 2h) and TNFα synergistically induces apoptosis in mouse lung epithelium. We extended this work by analyzing HS effects on human lung epithelial responses to clinically relevant injury. Cotreatment with TNFα and HS induced little caspase-3 and PARP cleavage in human small airway epithelial cells (SAECs) and A549 and BEAS2B cells. Scratch wound closure rates almost doubled when A549 and BEAS2B cells and air-liquid interface cultures of human bronchial epithelial (NHBE) were heat-shocked immediately post-wounding...
September 16, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Kenji Ishida, Emmitt R Jolly
Schistosomiasis is a debilitating disease that affects over 240 million people worldwide and is considered the most important neglected tropical disease following malaria. Free-swimming freshwater cercariae, one of the six morphologically distinct schistosome life stages, infect humans by directly penetrating through the skin. Cercariae identify and seek the host by sensing chemicals released from human skin. When they reach the host, they burrow into the skin with the help of proteases and other contents released from their acetabular glands and transform into schistosomula, the subsequent larval worm stage upon skin infection...
September 2016: PLoS Neglected Tropical Diseases
Peter Humburg, Narelle Maugeri, Wanseon Lee, Bert Mohr, Julian C Knight
BACKGROUND: The heat shock transcriptional response is essential to effective cellular function under stress. This is a highly heritable trait but the nature and extent of inter-individual variation in heat shock response remains unresolved. METHODS: We determined global transcription profiles of the heat shock response for a panel of lymphoblastoid cell lines established from 60 founder individuals in the Yoruba HapMap population. We explore the observed differentially expressed gene sets following heat shock, establishing functional annotations, underlying networks and nodal genes involving heat shock factor 1 recruitment...
2016: Genome Medicine
Daniel Zhang, Bin Zhang
HSF1 heat shock response has emerged as a valuable non-oncogenetic intervention point in targeted cancer therapy. Current reporter based high throughput screening has led to the discovery of several compounds or chemotypes that are effective in the growth inhibition of multiple cancer cell lines and relevant animal tumor models. However, some intrinsic limitations of reporter based assays can potentially lead to biased results. Using a previously validated high content image based assay, we performed a phenotypic screen targeting HSF1 heat shock pathway with a chemically diversified library of over 100,000 compounds...
September 30, 2016: Biochemical and Biophysical Research Communications
Anna Maikova, Zhanneta Zalutskaya, Tatiana Lapina, Elena Ermilova
The responses of Chlamydomonas reinhardtii cells to low temperatures have not been extensively studied compared with other stresses. Like other organisms, this green alga has heat shock protein 70s (HSP70s) that are located in chloroplast, mitochondrion and cytosol. To test whether temperature downshifts affected HSP70s synthesis, we used real-time PCR and protein gel blot analysis. C. reinhardtii cells exposed to cold stress show increased HSP70s mRNA levels. Genes encoding other components of HSP70 chaperone machines (e...
October 1, 2016: Journal of Plant Physiology
Yoko Igarashi, Kohta Ohnishi, Kazuhiro Irie, Akira Murakami
Zerumbone is a sesquiterpene present in Zinger zerumbet. Many studies have demonstrated its marked anti-inflammatory and anti-carcinogenesis activities. Recently, we showed that zerumbone binds to numerous proteins with scant selectivity and induces the expression of heat shock proteins (HSPs) in hepatocytes. To dampen proteo-toxic stress, organisms have a stress-responsive molecular machinery, known as heat shock response. Heat shock factor 1 (HSF1) plays a key role in this protein quality control system by promoting activation of HSPs...
2016: PloS One
Michelle Hussong, Christian Kaehler, Martin Kerick, Christina Grimm, Alexandra Franz, Bernd Timmermann, Franziska Welzel, Jörg Isensee, Tim Hucho, Sylvia Krobitsch, Michal R Schweiger
The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process...
August 17, 2016: Nucleic Acids Research
Anshika Goenka, Sonali Sengupta, Rajesh Pandey, Rashmi Parihar, Girish Chandra Mohanta, Mitali Mukerji, Subramaniam Ganesh
The heat shock response is a conserved defense mechanism that protects cells from physiological stress, including thermal stress. Besides the activation of heat-shock-protein genes, the heat shock response is also known to bring about global suppression of transcription; however, the mechanism by which this occurs is poorly understood. One of the intriguing aspects of the heat shock response in human cells is the transcription of satellite-III (Sat3) long non-coding RNAs and their association with nuclear stress bodies (nSBs) of unknown function...
October 1, 2016: Journal of Cell Science
Arabinda Mahanty, Gopal Krishna Purohit, Ravi Prakash Yadav, Sasmita Mohanty, Bimal Prasanna Mohanty
Changes in the expression of a number of hsp genes in minnow Puntius sophore collected from a hot spring run-off (Atri hot spring in Odisha, India; 20(o)09'N 85(°)18'E, 36-38 °C) were investigated to study the upper thermal acclimation response under heat stress, using same species from aquaculture ponds (water temperature 27 °C) as control. Expression of hsp genes was analyzed in both groups using RT-qPCR, which showed up-regulation of hsp90 (2.1-fold) and hsp47 (2.5-fold) in hot spring run-off fishes, whereas there was no alteration in expression of other hsps...
August 13, 2016: Fish Physiology and Biochemistry
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