Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma

Kubota, Hiroshi; Yamamoto, Soh; Itoh, Eri; Abe, Yuki; Nakamura, Asami; Izumi, Yukina; Okada, Hirotaka; Iida, Masatake; Nanjo, Hiroshi; Itoh, Hidenori; Yamamoto, Yūzō

doi:10.1007/s12192-010-0211-0

Cited by 86 publications

(84 citation statements)

References 38 publications

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“…Several recent studies also described increased expression of the co-chaperone HOP in specific cancers [4][5][6] and have suggested a down-regulation of CHIP [7]. Our study confirmed a decrease in overall survival of patients with higher levels of Hsp90α, Hsp90β and Hsp70 with the strongest effect of Hsp70.…”

Section: Discussionsupporting

confidence: 88%

“…Within the Hsp70/Hsp90 system, the co-chaperone HOP (Hsp70/Hsp90 organizing protein, also called STIP1, Stress-Inducible Protein 1) facilitates chaperoning activity of Hsp90 via simultaneous binding to both Hsp70 and Hsp90 to mediate the transfer of a client protein from Hsp70 to Hsp90 [3]. It has been observed that HOP is over-expressed in some cancers and is thought to have pro-tumorigenic properties [4][5][6]. Conversely, the co-chaperone CHIP (C terminus of Hsc70-interacting protein) is a chaperone-associated E3 ubiquitin ligase which targets unfolded proteins for degradation, and its down-regulation has been associated with advanced cancer and higher grade [7].…”

Section: Introductionmentioning

confidence: 99%

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Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

Růčková

Müller

Nenutil

et al. 2012

Cellular and Molecular Biology Letters

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Activation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Nonproliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/cochaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

Růčková

Müller

Nenutil

et al. 2012

Cellular and Molecular Biology Letters

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“…The molecular chaperone complex of Hop, Hsp70 and Hsp90 is involved in the folding and maturation of key regulatory proteins involved in cell viability [6], such as steroid hormone receptors, transcription factors and kinases (some of which are involved in cancer progression). The role of Hop in tumour progression is not fully elucidated; however, Hop has been shown to be over expressed in colonic carcinoma cells [7] and in hepatocellular carcinoma (HCC) [8]. Hop is secreted by and shown to induce proliferation in glioma tumour cells through MAPK and P13K pathways [9].…”

Section: Introductionmentioning

confidence: 99%

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

et al. 2011

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Keywords:Hop/STIP1/STI1 (Hsp70/Hsp90-organising protein) Pancreatic cancer Immunohistochemistry In vitro invasion MMP-2 a b s t r a c tWe previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered.In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours.Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

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“…Stress-induced-phosphoprotein 1 (STIP1) is an Hsp70/Hsp90-organizing protein, a co-chaperone that regulates the different functions of Hsps. STIP1 has been associated with several types of cancer (44)(45)(46)(47). PTGES3 or cytosolic prostaglandin E synthase is a 23 kDa glutathione-requiring enzyme expressed in a wide variety of cells.…”

Section: Discussionmentioning

confidence: 99%

Apigenin inhibits growth and induces apoptosis in human cholangiocarcinoma cells

et al. 2017

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Abstract.A promising nutraceutical, apigenin, was recently revealed to exhibit biological activity in inhibiting several types of cancer. The effects of apigenin on the growth inhibition and apoptosis of the cholangiocarcinoma HuCCA-1 cell line were investigated. Protein alterations subsequent to apigenin treatment were studied using a proteomic approach. The values of 20, 50 and 90% inhibition of cell growth (IC 20 , IC 50 and IC 90 ) were determined by MTT cell viability assay. Apoptotic cell death was detected using two different methods, a flow cytometric analysis (Muse Cell Analyzer) and DNA fragmentation assay. A number of conditions including attached and detached cells were selected to perform two-dimensional gel electrophoresis (2-DE) to study the alterations in the expression levels of treated and untreated proteins and identified by liquid chromatography (LC)/tandem mass spectrometry (MS/MS). The IC 20 , IC 50 and IC 90 values of apigenin after 48 h treatment in HuCCA-1 cells were 25, 75 and 200 µM, respectively, indicating the cytotoxicity of this compound. Apigenin induced cell death in HuCCA-1 cells via apoptosis as detected by flow cytometric analysis and exhibited, as confirmed with DNA fragmentation, characteristics of apoptotic cells. A total of 67 proteins with altered expression were identified from the 2-DE analysis and LC/MS/MS. The cleavage of proteins involved in cytoskeletal, cytokeratin 8, 18 and 19, and high expression of S100-A6 and S100-A11 suggested that apoptosis was induced by apigenin via the caspase-dependent pathway. Notably, two proteins, heterogeneous nuclear ribonucleoprotein H and A2/B1, disappeared completely subsequent to treatment, suggesting the role of apigenin in inducing cell death. The present study indicated that apigenin demonstrates an induction of growth inhibition and apoptosis in cholangiocarcinoma cells and the apoptosis pathway was confirmed by proteomic analysis.

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Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma

Cited by 86 publications

References 38 publications

Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

Apigenin inhibits growth and induces apoptosis in human cholangiocarcinoma cells

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