Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Noh, Hyunjin; Kim, Hyun J; Yu, Mi Ra; Kim, Wan-Young; Kim, Jin; Ryu, Jung Hwa; Kwon, Soon Hyo; Jeon, Jin Seok; Han, Dong Cheol; Ziyadeh, Fuad N.

doi:10.1038/labinvest.2012.127

Cited by 68 publications

(68 citation statements)

References 41 publications

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“…Hsp90 inhibitors often cause Hsp90 clients to be degraded via the proteasomal (77)(78)(79) or (less commonly) the autophagy (91) pathways. We found here that the autophagy inhibitor 3-MA partially increased EBV PK expression levels in the presence of 17-DMAG, while the proteasomal inhibitor had no effect.…”

Section: Discussionmentioning

confidence: 99%

“…Many Hsp90 client proteins are degraded via the ubiquitin-proteasome pathway in the absence of Hsp90 (77)(78)(79), suggesting that proteasomal inhibitors might attenuate the effect of the Hsp90 inhibitor on EBV PK and/or HCMV UL97 expression. In addition to the ubiquitin-proteasome pathway, the autophagy pathway is another important protein degradation pathway and has been shown to mediate the degradation of a subset of Hsp90 client proteins (80)(81)(82)(83).…”

Section: -Dmag Treatment Inhibits Intracellular Lytic Viral Replicamentioning

confidence: 99%

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Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Sun

Bristol

Iwahori

et al. 2013

J Virol

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H uman herpesviruses are enveloped viruses containing relatively large, double-stranded DNA genomes. Although all herpesviruses experience both latent and lytic stages of infection, they are grouped into three separate families (alpha-, beta-, and gammaherpesviruses) according to differences in sequence homology and cellular tropisms. The alphaherpesviruses, which comprise herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), cause recurrent skin lesions and meningitis (1, 2). Human cytomegalovirus (HCMV), human herpesviruses 6A and 6B (HHV6), and human herpesvirus 7 (HHV7) are betaherpesviruses, which cause severe disease in patients with compromised immune function (3, 4). The gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are causally associated with mononucleosis (EBV) as well as a variety of human cancers (5, 6).Each of the eight human herpesviruses encodes a protein kinase (PK) with discernible homology in amino acid sequences and positional similarity in their respective viral genomes. These related protein kinases, termed the conserved herpesvirus protein kinases (CHPKs), are important for viral replication and infection (7-13). They play important roles in multiple processes, including gene expression (8,11,14), viral DNA replication (11,(15)(16)(17), capsid nuclear egress (7,11,18,19), and the DNA damage response (20, 21). For example, EBV PK (the product of the BGLF4 gene) phosphorylates a number of different viral and cellular proteins, including the viral DNA polymerase processivity factor BMRF1 (7,(22)(23)(24); the latent viral proteins EBNA1 (25), EBNA2 (26), and EBNA LP (27); the EBV immediate early (IE) protein BZLF1 (28); the cell cycle regulatory proteins p27 (29) and pRB (30); nuclear lamin A/C (7, 31); and interferon regulatory factor 3 (IRF3) (32). In addition, EBV PK may upregulate the expression of two viral proteins important for nuclear egress, BFRF1 and BFLF2 (11,33). Both EBV PK and the homologous HCMV kinase, UL97, greatly enhance but are not absolutely required for the release of infectious viral particles in vitro and appear to be intimately involved in the pathogenesis associated with viral infections in vivo (34,35). Although maribavir, an inhibitor of HCMV UL97, failed a phase III clinical trial in bone marrow transplant patients (36) (possibly due to insufficient dosing), CHPKs nevertheless remain very promising targets for development of novel antiviral therapeutics.Two guanine nucleoside analogues, ganciclovir (GCV) and acyclovir (ACV), have been used frequently to inhibit replication of various human herpesviruses by targeting viral DNA polymerases (37-40). UL97 mediates the first step of GCV and ACV phosphorylation (41-43). Since the triphosphorylated forms of GCV and ACV are much better substrates for herpesvirus DNA polymerases than cellular DNA polymerases, GCV and ACV inhibit viral DNA replication more effectively than cellular DNA replication (44,45). It was recently found that EBV PK is req...

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Section: Discussionmentioning

confidence: 99%

Section: -Dmag Treatment Inhibits Intracellular Lytic Viral Replicamentioning

confidence: 99%

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Sun

Bristol

Iwahori

et al. 2013

J Virol

View full text Add to dashboard Cite

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“…Most HSPs play important roles as protein chaperones, regulators of protein folding, regulators of protein degradation, and supporters of protein complex formation [37,38]. Recently, several HSPs have been shown to be involved in EMT in renal tubular epithelial cells [39][40][41], lung cells [42], and prostate cancer cells [43]. While there is some agreement regarding the characteristics of HSPs, their effect on EMT remains controversial.…”

Section: Hyperthermia Inhibits Tgf-β-induced Emt In Pancreatic Cancermentioning

confidence: 99%

“…For example, HSP72 has been shown to inhibit TGF-β1-induced EMT in renal epithelial cells by preventing TGF-β1-induced phosphorylation and nuclear translocation of Smad and p-Smad [39,40]. In contrast, Noh H. et al [41] reported that HSP90 inhibitor blocks TGF-β1-induced Smad phosphorylation and induces the degradation of the TGF-β type II receptor, thereby preventing TGF-β-stimulation from inducing EMT. HSP27 is considered to be a component of several pathways known to induce EMT in prostate cancer, including the IL-6/STAT3 pathway [43].…”

Section: Hyperthermia Inhibits Tgf-β-induced Emt In Pancreatic Cancermentioning

confidence: 99%

Inhibition of Epithelial-to-Mesenchymal Transition (EMT) by Hyperthermia

Kokura

2016

Hyperthermic Oncology From Bench to Bedside

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Hyperthermia therapy suppresses tumor growth through deliberate heating. To further enhance the antitumor effect, it is often combined with radiation or chemotherapy. In addition, hyperthermia may reduce the metastatic potential of cancer cells and inhibit tumor metastasis. However, the underlying mechanisms through which hyperthermia inhibits cancer metastasis have yet to be fully elucidated. Epithelial-to-mesenchymal transition (EMT) plays a key role in tumor metastasis; therefore, the aim of this chapter is to summarize the effects and underlying mechanisms of EMT in cancer cells. The results suggest that hyperthermia not only inhibits tumor growth, but also mediates the expression of EMT-related genes-including E-cadherin and vimentin-and a number of transcription factors important for cancer cell motility, invasiveness, and metastasis during tumorigenesis. Furthermore, hyperthermia may also reverse alterations in cell morphology induced by transforming growth factor-β (TGF-β) and/or hypoxia, as well as the increased cell invasiveness characteristic of EMT. Taken together, these data indicate that hyperthermia suppresses cancer migration and invasion through the inhibition of EMT. Keywords EMT • E-cadherin • Vimentin • TGF-β Hyperthermia and MetastasesHyperthermia is a therapeutic method that suppresses tumor growth through the deliberate heating of a primary tumor. The antitumor effect of hyperthermia is enhanced when used in combination with radiation or chemotherapy. Moreover, a previous study in an animal model demonstrated that local hyperthermia can inhibit tumor metastasis [1], and a clinical trial demonstrated that local hyperthermia could be effective for treating cervical lymph node metastasis in oral cancer [2]. In addition, in our previous study, we reported the potential of hyperthermia for

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“…Our recent findings (26) as well as those of other groups have indicated that Hsp90 is a critical modulator of fibrosis via alteration of the TGF␤ signaling pathway (27)(28)(29)(30). To further develop this line of research, the present study was designed to look into the possible role of Hsp90 in STAT-3-mediated fibrotic signaling during cardiac hypertrophy and associated fibrosis.…”

mentioning

confidence: 94%

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Datta

Bansal

Rana

et al. 2017

Molecular and Cellular Biology

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Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Cited by 68 publications

References 41 publications

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Inhibition of Epithelial-to-Mesenchymal Transition (EMT) by Hyperthermia

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

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