hsp90 expression
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Author(s):  
Xin Tang ◽  
Cheng Chang ◽  
Daniel Mosallaei ◽  
David T. Woodley ◽  
Axel H. Schönthal ◽  
...  

The rare capacity for heat shock protein-90 (Hsp90) chaperones to support almost the entire cellular signaling networks was viewed as a potential breakthrough point to combat tumor resistance to single oncogene-based therapeutics. Over two decades, several generations of Hsp90 ATP-binding inhibitors have entered numerous cancer clinical trials, but few have advanced to FDA approval for treatment of human cancers. Herein, we report that Hsp90 expression dramatically vary especially among different types of non-cancer cells and organs. The highly variable levels of Hsp90 from as low as 1.7% to as high as 9% of their total cellular proteins were responsible for either an extreme sensitivity or an extreme resistance to a classical Hsp90 ATP-binding inhibitor. Among randomly selected cancer cell lines, the same client proteins for regulation of cell growth exhibited unexpectedly heterogenous reactions in response to Hsp90 ATP-binding inhibitor, inconsistent with the current understanding. Finally, a minimum amount (<10%) of Hsp90β was still required for client protein stability and cell survival even in the presence of full Hsp90α. These new findings of Hsp90 expression in host and isoform compensation in tumor cells could complicate biomarker selection, toxicity readout and clinical efficacy of Hsp90-ATP-binding inhibitors in cancer clinical trials.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jéssica A. Troiano ◽  
Simone R. Potje ◽  
Murilo E. Graton ◽  
Emily T. Gonçalves ◽  
Rita C. Tostes ◽  
...  

We have investigated the role caveolae/caveolin-1 (Cav-1) plays in endothelial nitric oxide synthase (eNOS) activation and how it impacts pregnancy-induced decreased vascular reactivity in normotensive (Wistar rats) and spontaneously hypertensive rats (SHR). Wistar rats and SHR were divided into non-pregnant (NP) and pregnant (P). Nitrite levels were assessed by the Griess method in the aorta and mesenteric vascular bed. In functional studies, arteries were incubated with methyl-β-cyclodextrin (dextrin, 10mmol/L), which disrupts caveolae by depleting cholesterol, and concentration-response curves to phenylephrine (PE) and acetylcholine (ACh) were constructed. Electronic microscopy was used to determine endothelial caveolae density in the aorta and resistance mesenteric artery in the presence of vehicle or dextrin (10mmol/L). Western blot was performed to evaluate Cav-1, p-Cav-1, calmodulin (CaM), and heat shock protein 90 (Hsp90) expression. Cav-1/eNOS interaction in the aorta and mesenteric vascular bed was assessed by co-immunoprecipitation. Nitric oxide (NO) generation was greater in arteries from P groups compared to NP groups. Dextrin did not change vascular responses in the aorta from P groups or the number of caveolae in P groups compared to NP groups. Compared to NP Wistar rats, NP SHR showed smaller number of caveolae and reduced Cav-1 expression. Pregnancy did not alter Cav-1, CaM, or Hsp90 expression in the aorta or mesenteric vascular bed from Wistar rats or SHR. These results suggest that pregnancy does not alter expression of the main eNOS regulatory proteins, but it decreases Cav-1/eNOS interaction. Reduced Cav-1/eNOS interaction in the aorta and mesenteric vascular bed seems to be an important mechanism to increase eNOS activity and nitric oxide production in pregnant normotensive and hypertensive rats.


2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Wenwen Zhou ◽  
Yanhong Yang ◽  
Zhenzhen Wang ◽  
Yan Liu ◽  
Moslem Lari Najafi

Lung cancer is a lethal disease, and early diagnosis with the aid of biomarkers such as HSP90α protein can certainly assist the doctors to start treatment of patient at the earliest and can save their lives. To analyse the diagnostic value of HSP90α expression in lung cancer patients by collecting data of patients through IoT devices to avoid delay in treatments, a study has been presented in this paper where the significance of HSP90α biomarker is highlighted in early diagnosis of patients suffering from lung cancer. The second objective of the research study is to examine the correlation between the appearance level of HSP90α biomarker and the clinicopathological features of lung cancer. It is also evaluated whether the changes in HSP90α index are indicative or noteworthy before and after surgery of lung cancer patients. An observatory study of 78 patients with lung cancer in Qinhuangdao Hospital is presented in this paper where the samples were collected from June 2018 to March 2020. Their data were collected through IoT devices used in the latest healthcare facilities of the hospital. The ELISA method was utilized to identify the level of plasma HSP90 and to analyse HSP90 levels between the lung cancer group and healthy group of people. The relationship between HSP90 and the clinical pathological features of 78 patients suffering from lung cancer was analysed. An electrochemical luminescence method was used to detect CEA, NSE, SCC, and CYFRA21-1 levels. ROC curve and box plots were used to determine the analytic value of HSP90 and other biomarkers used in lung cancer diagnosis. Forty-two patients with moderate to early stage lung cancer with surgical correction were selected, and paired sample T test was used to analyse HSP90 levels before and after surgery. The plasma HSP90 level of lung cancer patients was quite higher as compared to the group of healthy people as per the values depicted in the research study. Second, HSP90 levels are substantially higher in pathologic type, differentiation degree, stage, and the existence of the lung, liver, and bone metastases ( P  < 0.05). The level of HSP90 expression was largely impacted by a few factors such as sex, age, smoking, and tumour location ( P  > 0.05). The ROC value for HSP90 was 0.599, while the area under the curve of HSP90 combined with other four tumour markers was 0.915 in the presented case study, indicating the presence of lung cancer. Patients with lung cancer had statistically significant differences in HSP90 expression levels before and after surgery ( P  < 0.05). It is concluded that the expression level of plasma HSP90α in lung cancer patients increases remarkably; therefore, HSP90 can be used to monitor presence of lung cancer before and after surgery in the patients.


2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jie Zeng ◽  
Si-Li He ◽  
Li-Jie Li ◽  
Chen Wang

Abstract Background HPV16 is the predominant cancer-causing strain that is responsible for over 50% of all cervical cancers. In this study, we aim to investigate the therapeutic effect of heat shock protein 90 (Hsp90) knockdown on HPV16+ cervical cancer progression and the underlying mechanism. Methods The transcript and protein expression of Hsp90 in normal cervical and HPV16+ cervical cancer tissues and cell lines were detected by qRT-PCR, immunohistochemistry staining and Western blot. Hsp90 knockdown clones were established using HPV16+ cervical cancer cell line Caski and SiHa cells. The effect of Hsp90 knockdown on HER2/PI3K/AKT pathway and PD-L1 expression was characterized using qRT-PCR and Western blot analysis. Cell proliferation and migration were determined using MTT and transwell assays. Using mouse xenograft tumor model, the impact of Hsp90 knockdown and PD-L1 overexpression on tumor progression was evaluated. Results Hsp90 expression was up-regulated in HPV16+ cervical cancer tissues and cells. Knockdown of Hsp90 inhibited proliferation and migration of Caski and SiHa cells. PD-L1 expression in cervical cancer tissues was positively correlated with Hsp90 expression, and Hsp90 regulated PD-L1 expression via HER2/PI3K/AKT signaling pathway. The results of mouse xenograft tumor model demonstrated Hsp90 knockdown suppressed tumor formation and overexpression of PD-L1 simultaneously eliminated the cancer-suppressive effect of Hsp90 knockdown. Conclusion In this study, we demonstrated a promising tumor-suppressive effect of Hsp90 knockdown in HPV16+ cervical cancers, and investigated the underlying molecular pathway. Our results suggested that Hsp90 knockdown holds great therapeutic potential in treating HPV16+ cervical cancers.


Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1034
Author(s):  
Tanya Ju-Ngam ◽  
Nichanun McMillan ◽  
Mamoru Yoshimizu ◽  
Hisae Kasai ◽  
Ratree Wongpanya ◽  
...  

The aims of this research were to perform molecular characterization and biofunctional analyses of giant river prawn Hsp40 and Hsp90 genes (Mr-hsp40 and Mr-hsp90) under various stress conditions. Comparisons of the nucleotide and amino acid sequences of Mr-hsp40 and Mr-hsp90 with those of other species showed the highest similarity scores with crustaceans. Under normal conditions, expression analysis using quantitative real-time RT-PCR (qRT-PCR) indicated that Mr-hsp40 was highly expressed in the gills and testis, and Mr-hsp90 expression was observed in all tissues, with the highest expression in the ovary. The expression patterns of Mr-hsp40 and Mr-hsp90 transcripts under Aeromonas hydrophila challenge and heat–cold shock conditions were examined in gills, the hepatopancreas and hemocytes, at 0, 3, 6, 12, 24, 48 and 96 h by qRT-PCR. Under bacterial challenge, Mr-hsp40 displayed variable expression patterns in all tissues examined during the tested periods. In contrast, upregulated expression of Mr-hsp90 was quickly observed from 3 to 12 h in the gills and hepatopancreas, whereas obviously significant upregulation of Mr-hsp90 was observed in hemocytes at 12–96 h. Under temperature shock conditions, upregulation of Mr-hsp40 expression was detected in all tested tissues, while Mr-hsp90 expression was quickly upregulated at 3–48 h in all tissues in response to 35 °C conditions, and conditions of 35 and 25 °C stimulated its expression in gills and the hepatopancreas at 12 and 48 h, respectively. Silencing analyses of these two genes were successfully conducted under normal, high-temperature (35 °C) and A. hydrophila infection conditions. Overall, knockdown of Mr-hsp40 and Mr-hsp90 effectively induced more rapid and higher mortality than in the PBS control and GFP induction groups in temperature and infectious treatments. Evidence from this study clearly demonstrated the significant functional roles of Mr-hsp40 and Mr-hsp90, which are crucially involved in cellular stress responses to both temperature and pathogenic bacterial stimuli.


2021 ◽  
pp. 194589242110128
Author(s):  
Jingjing Wang ◽  
Li Hu ◽  
Zhuofu Liu ◽  
Huan Wang ◽  
Huankang Zhang ◽  
...  

Background Juvenile nasopharyngeal angiofibroma (JNA) is a highly recurrent tumor after curative surgery. Objective The purpose of this study was to evaluate heat shock protein 90 (HSP90) expression in JNA and its association with tumor recurrence. Methods Immunohistochemistry was performed to assess HSP90 expression using tissue microarrays containing 70 JNA patients and 10 control subjects. The associations of HSP90 expression with clinicopathological features and tumor recurrence were analyzed. Results Immunohistochemistry revealed high HSP90 expression in JNA compared with normal middle turbinate samples. High expression of HSP90, which correlated with MVD ( P = .001), ER-α ( P = .001), VEGF ( P < .001) and JNA recurrence ( P = .009), was an independent prognostic factor of time to recurrence ( P = .017). The combination of HSP90 and ER-α had a better power to predict disease recurrence than other clinicopathological features ( P = .008). Conclusions HSP90 may be an independent prognostic marker in JNA patients administered surgical treatment. Combination of HSP90 and ER-α expression may be the best predictor of tumor recurrence among all clinicopathological factors.


PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001197
Author(s):  
Jiajun Huang ◽  
Xiaoyu Zhao ◽  
Xiang Li ◽  
Jiwei Peng ◽  
Weihao Yang ◽  
...  

Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.


2021 ◽  
Vol 28 ◽  
Author(s):  
Chih-Shiang Chang ◽  
Vathan Kumar ◽  
Der-Yen Lee ◽  
Yeh Chen ◽  
Yu-Chieh Wu ◽  
...  

Background: A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease. Method: We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo-fused N-heterocycle. Results: Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC50 as low as 0.25 µM) versus nontumorigenic MCF-10A breast epithelial cells (IC50 ≥ 5 µM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70’s, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation. Conclusion: Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear, which is currently under investigation.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yifeng Ke ◽  
Xiaoe Fan ◽  
Rui Hao ◽  
Lijie Dong ◽  
Min Xue ◽  
...  

Abstract Objective Retinal degenerative diseases remain the dominant causes of blindness worldwide, and cell replacement is viewed as a promising therapeutic direction. However, the resources of seed cells are hard to obtain. To further explore this therapeutic approach, human embryonic stem extracellular vesicles (hESEVs) were extracted from human embryonic stem cells (hESCs) to inspect its effect and the possible mechanism on retinal Müller cells and retinal function. Methods hESEVs were extracted by multi-step differential centrifugation, whose morphologies and specific biomarkers (TSG101, CD9, CD63, and CD81) were observed and measured. After hESEVs were injected into the vitreous cavity of RCS rats, the retinal tissues and retinal functions of rats were assessed. The alteration of Müller cells and retinal progenitor cells was also recorded. Microvesicles (MVs) or exosomes (EXOs) were extracted from hESCs transfected with sh-HSP90 or pcDNA3.1-HSP9, and then incubated with Müller cells to measure the uptake of EVs, MVs, or EXOs in Müller cells by immunofluorescence. The retrodifferentiation of Müller cells was determined by measuring Vimentin and CHX10. qRT-PCR and western blot were used to detect HSP90 expression in MVs and evaluate Oct4 level in Müller cells, and Co-IP to inspect the interaction of HSP90 and Oct4. Results RCS rats at the postnatal 30 days had increased retinal progenitor cells which were dedifferentiated from Müller cells. hESEVs were successfully extracted from hESCs, evidenced by morphology observation and positive expressions of specific biomarkers (TSG101, CD9, CD63, and CD81). hESEVs promoted Müller cells dedifferentiated and retrodifferentiated into retinal progenitor cells evidenced by the existence of a large amount of CHX10-positive cells in the retinal inner layer of RCS rats in response to hESEV injection. The promotive role of hESEVs was exerted by MVs demonstrated by elevated fluorescence intensity of CHX10 and suppressed Vimentin fluorescence intensity in MVs rather than in EXOs. HSP90 in MVs inhibited the retrodifferentiation of Müller cells and suppressed the expression level of Oct4 in Müller cells. Co-IP revealed that HSP90 can target Oct4 in Müller cells. Conclusion hESEVs could promote the retrodifferentiation of Müller cells into retinal progenitor cells by regulating the expression of Oct4 in Müller cells by HSP90 mediation in MVs.


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