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hsp70 cancer

Ju Hui Jeong, Yong Jin Oh, Taeg Kyu Kwon, Young Ho Seo
The molecular chaperone Hsp90 has emerged as an attractive cancer therapeutic target due to its role in cellular homeostasis by modulating the stabilization and maturation of many oncogenic proteins. In this study, we designed and synthesized a series of Hsp90 inhibitors that hybridized NVP-AUY992 (2) and PU3 (3) in the chalcone scaffold using a structure-based approach. Our results indicate that compound 1g inhibited the proliferation of gefitinib-resistant non-small cell lung cancer (H1975) cells, downregulated the expression of client proteins of Hsp90 including EGFR, MET, Her2 and Akt, and up-regulated the expression of Hsp70...
October 21, 2016: Archives of Pharmacal Research
Schammim Ray Amith, Krista Marie Vincent, Jodi Marie Wilkinson, Lynne Marie Postovit, Larry Fliegel
Mounting evidence supports a major role for the Na(+)/H(+) exchanger NHE1 in cancer progression and metastasis. NHE1 is hyperactive at the onset of oncogenic transformation, resulting in intracellular alkalinization and extracellular microenvironmental acidification. These conditions promote invasion and facilitate metastasis. However, the signal pathways governing the regulation of exchanger activity are still unclear. This is especially important in the aggressively metastatic, triple-negative basal breast cancer subtype...
October 15, 2016: Cellular Signalling
Ruifang Zheng, George P Studzinski
Differentiation therapy can supplement the therapy of APL, but other subtypes of AML are treated principally with cytotoxic agents, with few lasting remissions. While the induction of monocyte followed by macrophage differentiation by vitamin D derivatives (VDDs) is dramatic in cultured AML cells of all subtypes, attempts to translate this to the clinic have not been effective. Thus, better understanding of the mechanisms underlying VDD-induced differentiation may improve this approach. The key events in this form of differentiation include increased expression of CD11b, and the transcription factor PU...
October 17, 2016: Leukemia & Lymphoma
Xiao-Ping Wang, Qiao-Xia Wang, Huan-Ping Lin, Bing Xu, Qian Zhao, Kun Chen
Alpha-fetoprotein (AFP) is a marker of hepatocellular carcinoma (HCC) and serves as a target for immunotherapy. However, current treatments targeting AFP are not reproducible and do not provide complete protection against cancer. This issue may be solved by developing novel therapeutic vaccines with enhanced immunogenicity that could effectively target AFP-expressing tumors. In this study, we report construction of a therapeutic peptide vaccine by linking heat shock protein 70 (HSP70) functional peptide to the AFP epitope to obtain HSP70-P/AFP-P...
October 4, 2016: Oncotarget
Alan M Jones, Isaac M Westwood, James D Osborne, Thomas P Matthews, Matthew D Cheeseman, Martin G Rowlands, Fiona Jeganathan, Rosemary Burke, Diane Lee, Nadia Kadi, Manjuan Liu, Meirion Richards, Craig McAndrew, Norhakim Yahya, Sarah E Dobson, Keith Jones, Paul Workman, Ian Collins, Rob L M van Montfort
The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors...
October 6, 2016: Scientific Reports
Madaras Balázs, Horváth Zsolt, Gráf László, Gálffy Gabriella, Tamási Lilla, Ostoros Gyula, Döme Balázs, Mórocz Éva, Bártfai Zoltán, Prohászka Zoltán, Kocsis Judit
The 70 kDa heat shock protein (Hsp70) is a highly conservative molecular chaperone, that has important role in cell integrity. Recently considerable amount of data are accumulating on the potential role of Hsp70 in carcinogenesis and tumor progression. Most papers are focusing on intracellular or membrane bound protein, however very limited data exist on serum Hsp70, that can also induce innate and adaptive immune response. Previously we have published data on the correlation between coloretal cancer progression and serum Hsp70 concentration...
October 4, 2016: Pathology Oncology Research: POR
Chi Zhang, Xin Wang, Hongchun Liu, Minmin Zhang, Meiyu Geng, Liping Sun, Aijun Shen, Ao Zhang
A structure-based medicinal chemistry optimization was conducted on the clinical Hsp90 inhibitor diarylisoxazole 3. Several series of new compounds were designed and synthesized by incorporating diversified amino acid derivatives with various lengths to the 3-amido motif of the isoxazole scaffold. Compound 14j was identified to have high Hsp90 binding potency (14 nM) and antiproliferative activity against H3122 human lung cancer and BT-474 breast cancer cells. Treatment of 14j with H3122 cell led to degradation of client protein ALK, reduction of downstream phosphorylation of AKT and ERK, and up-regulation of Hsp70...
September 16, 2016: European Journal of Medicinal Chemistry
Ingo Amm, Mona Kawan, Dieter H Wolf
Protein misfolding and protein aggregation are causes of severe diseases as neurodegenerative disorders, diabetes and cancer. Therefore, the cell has to constantly monitor the folding status of its proteome. Chaperones and components of the ubiquitin-proteasome system are key players in the cellular protein quality control process. In order to characterize components of the protein quality control system in a well-established model eukaryote - the yeast Saccharomyces cerevisiae - we established new cytosolic model substrates based on firefly luciferase and β-isopropylmalate dehydrogenase (Leu2)...
December 15, 2016: Analytical Biochemistry
Shanshan Liu, Timothy O Street
The molecular chaperone Hsp90 facilitates the folding and modulates activation of diverse substrate proteins. Unlike other heat shock proteins such as Hsp60 and Hsp70, Hsp90 plays critical regulatory roles by maintaining active states of kinases, many of which are overactive in cancer cells. Four Hsp90 paralogs are expressed in eukaryotic cells: Hsp90α/β (in the cytosol), Grp94 (in the endoplasmic reticulum), Trap1 (in mitochondria). Although numerous Hsp90 inhibitors are being tested in cancer clinical trials, little is known about why different Hsp90 inhibitors show specificity among Hsp90 paralogs...
September 26, 2016: Protein Science: a Publication of the Protein Society
Jian Li, Yun Xing, Zhenxian Zhou, Wenjun Yao, Rongyue Cao, Taiming Li, Maolei Xu, Jie Wu
Tumor-derived autophagome (DRibble) is an effective therapeutic cancer vaccine inducing T cell recognition and death of tumor cells in mice. However, the potential for improved anti-tumor response still remains. Our previous study demonstrated that two repeats of a mycobacterial HSP70407-426 (M2) peptide acted as adjuvant in improving anti-tumor efficacy of human umbilical vein endothelial cell (HUVEC) vaccine. Here, a DRibble vaccine conjugated with M2 (DRibble-M2) was designed as a novel vaccine to enhance anti-tumor activity...
September 23, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Nirmala Jagadish, Sumit Agarwal, Namita Gupta, Rukhsar Fatima, Sonika Devi, Vikash Kumar, Vaishali Suri, Rajive Kumar, Vitusha Suri, Trilok Chand Sadasukhi, Anju Gupta, Abdul S Ansari, Nirmal Kumar Lohiya, Anil Suri
BACKGROUND: Breast cancer is one of the leading cause of cancer-related deaths in women worldwide and increasing rapidly in developing countries. In the present study, we investigated the potential role and association of HSP70-2 with breast cancer. METHODS: HSP70-2 expression was examined in 154 tumor and 103 adjacent non-cancerous tissue (ANCT) specimens and breast cancer cell lines (MCF7, BT-474, SK-BR-3 and MDA-MB-231) by RT-PCR, quantitative-PCR, immunohistochemistry, Western blotting, flow cytometry and indirect immunofluorescence...
September 22, 2016: Journal of Experimental & Clinical Cancer Research: CR
Khaldon Bodoor, Sara Abu Jalboush, Ismail Matalka, Aya Abu-Sheikha, Rofieda Al Waq, Hanadi Ebwaini, Aymen Abu-Awad, Luma Fayyad, Jamal Al-Arjat, Yazan Haddad
Gastric cancer (GC) is a major health problem worldwide and is one of the ten most commonly diagnosed cancers in Jordan. GC is usually diagnosed at late aggressive stages in which treatment options are limited. Recently, heat shock proteins (HSPs) found to be overexpressed in a wide range of malignancies have been considered as promising candidate biomarkers for GC. The aim of this study was to investigate pathogenic roles of a panel of cytosolic HSPs including HSP90, HSP70, HSP60 and HSP27 in GC. Immunohistochemistry was used to assess the level of expression of these proteins in archived tumor samples (N=87) representing various pathological characteristics of GC...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
Sri Sulistyowati, Adhitya Ardhianto, Syamsul Hadi
This study aims to analyze the effect of logotherapy on the expression of cortisol, HSP70, and the Beck Depression Inventory (BDI) and to conduct pain assessments in advanced cervical cancer patients. We carried out this research through pretest-posttest control-group design on the expression of cortisol, HSP70, the BDI, and pain scales after a patient receives logotherapy treatment. Based on a comparative test conducted with the two groups before the treatment, there is no significant difference (p > .05)...
September 20, 2016: Health Care for Women International
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
Jonathan Asling, Jodi Morrison, Anthony J Mutsaers
Heat shock proteins (HSPs) are molecular chaperones subdivided into several families based on their molecular weight. Due to their cytoprotective roles, these proteins may help protect cancer cells against chemotherapy-induced cell death. Investigation into the biologic activity of HSPs in a variety of cancers including primary bone tumors, such as osteosarcoma (OSA), is of great interest. Both human and canine OSA tumor samples have aberrant production of HSP70. This study assessed the response of canine OSA cells to inhibition of HSP70 and GRP78 by the ATP-mimetic VER-155008 and whether this treatment strategy could sensitize cells to doxorubicin chemotherapy...
September 8, 2016: Cell Stress & Chaperones
Jinghai Hu, Fei Ye, Miao Cui, Peng Lee, Chengguo Wei, Yuanyuan Hao, Xiaoqing Wang, Yanbo Wang, Zhihua Lu, Matthew Galsky, Russell McBride, Li Wang, Dongwen Wang, Carlos Cordon-Cardo, Chunxi Wang, David Y Zhang
This study aimed to detect protein changes that can assist to understand the underlying biology of bladder cancer. The data showed forty five proteins were found to be differentially expressed comparing tumors vs non-tumor tissues, of which EGFR and cdc2p34 were correlated with muscle invasion and histological grade. Ten proteins (ß-catenin, HSP70, autotaxin, Notch4, PSTPIP1, DPYD, ODC, cyclinB1, calretinin and EPO) were able to classify muscle invasive BCa (MIBC) into 2 distinct groups, with group 2 associated with poorer survival...
2016: PloS One
Stefania Di Blasio, Inge M N Wortel, Diede A G van Bladel, Laura E de Vries, Tjitske Duiveman-de Boer, Kuntal Worah, Nienke de Haas, Sonja I Buschow, I Jolanda M de Vries, Carl G Figdor, Stanleyson V Hato
Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1)...
August 2016: Oncoimmunology
P Fonseca, I Vardaki, A Occhionero, T Panaretakis
Extracellular vesicles have gained tremendous attention in the recent years as a novel mechanism of cell to cell communication. There are several types of extracellular vesicles, including exosomes, microvesicles, exosome, like vesicles, apoptotic bodies that differ mainly in the mechanism of biogenesis and secretion. The most well studied type of extracellular vesicles are the exosomes which are endosome-derived vesicles with a diameter of 50-150nm and enriched in ESCRT proteins including Alix, TSG101, Hsp70, and tetraspanins...
2016: International Review of Cell and Molecular Biology
J S J Tan, K C Ong Kc, A Rhodes
Heat shock proteins (HSPs) are a family of evolutionary conserved proteins that work as molecular chaperones for cellular proteins essential for cell viability and growth as well as having numerous cyto-protective roles. They are sub-categorised based on their molecular weights; amongst which some of the most extensively studied are the HSP90 and HSP70 families. Important members of these two families; Heat shock proteins 70 and heat shock proteins 90 (Hsp70/90), are the glucose regulated proteins (GRP). These stress-inducible chaperones possess distinct roles from that of the other HSPs, residing mostly in the endoplasmic reticulum and mitochondria, but they can also be translocated to other cellular locations...
August 2016: Malaysian Journal of Pathology
Kai-Lin Yang, Cheng-Chung Huang, Mau-Shin Chi, Hsin-Chien Chiang, Yu-Shan Wang, Chien-Chung Hsia, Gabor Andocs, Hsin-Ell Wang, Kwan-Hwa Chi
Radiofrequency-induced hyperthermia (HT) treatments for cancer include conventional capacitive coupling hyperthermia (cCHT) and modulated electro-hyperthermia (mEHT). In this study, we directly compared these methods with regard to in vitro cytotoxicity and mechanisms of action under isothermal conditions. Hepatoma (HepG2) cells were exposed to HT treatment (42°C for 30 min) using mEHT, cCHT or a water bath. mEHT produced a much higher apoptosis rate (43.1% ± 5.8%) than cCHT (10.0% ± 0.6%), the water bath (8...
August 20, 2016: Oncotarget
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