Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

Baindur-Hudson, Swati; Edkins, Adrienne L.; Blatch, Gregory L.

doi:10.1007/978-3-319-11731-7_3

Cited by 55 publications

(39 citation statements)

References 151 publications

(173 reference statements)

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“…An alternative approach consists in the use of small molecule inhibitors that disrupt protein-protein interactions in the HSP90 chaperone machinery [37]. Recent evidence indicates that small compounds or peptides that interfere with the interaction between the TPR2A domain of STIP1 and the MEEVD motif of HSP90 can display anti-cancer activity both in vitro and in vivo [38]. These results suggest the potential usefulness of alternative strategies in the development of novel HSP90 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells

et al. 2016

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Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.

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Section: Discussionmentioning

confidence: 99%

Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells

et al. 2016

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“…Depleting PrP C inhibits growth, promotes programmed cell death in gliomas [13], and sensitizes tumor cells to cytotoxic drugs [14]. Likewise, HOP expression correlates with tumor progression [15], and is associated with proliferation [16, 17], invasion [17], and poor patient prognosis [18], and HOP has been described as an important regulator of tumor maintenance [19–21]. Recent findings show that HOP-PrP C binding modulates migration and invasion of colorectal cancer cells [22].…”

Section: Introductionmentioning

confidence: 99%

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Iglesia¹,

Prado

Cruz

et al. 2017

Stem Cell Res Ther

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BackgroundGlioblastoma (GBM), a highly aggressive brain tumor, contains a subpopulation of glioblastoma stem-like cells (GSCs) that play roles in tumor maintenance, invasion, and therapeutic resistance. GSCs are therefore a promising target for GBM treatment. Our group identified the cellular prion protein (PrPC) and its partner, the co-chaperone Hsp70/90 organizing protein (HOP), as potential target candidates due to their role in GBM tumorigenesis and in neural stem cell maintenance.MethodsGSCs expressing different levels of PrPC were cultured as neurospheres with growth factors, and characterized with stem cells markers and adhesion molecules markers through immunofluorescence and flow cytometry. We than evaluated GSC self-renewal and proliferation by clonal density assays and BrdU incorporation, respectively, in front of recombinant HOP treatment, combined or not with a HOP peptide which mimics the PrPC binding site. Stable silencing of HOP was also performed in parental and/or PrPC-depleted cell populations, and proliferation in vitro and tumor growth in vivo were evaluated. Migration assays were performed on laminin-1 pre-coated glass.ResultsWe observed that, when GBM cells are cultured as neurospheres, they express specific stemness markers such as CD133, CD15, Oct4, and SOX2; PrPC is upregulated compared to monolayer culture and co-localizes with CD133. PrPC silencing downregulates the expression of molecules associated with cancer stem cells, upregulates markers of cell differentiation and affects GSC self-renewal, pointing to a pivotal role for PrPC in the maintenance of GSCs. Exogenous HOP treatment increases proliferation and self-renewal of GSCs in a PrPC-dependent manner while HOP knockdown disturbs the proliferation process. In vivo, PrPC and/or HOP knockdown potently inhibits the growth of subcutaneously implanted glioblastoma cells. In addition, disruption of the PrPC-HOP complex by a HOP peptide, which mimics the PrPC binding site, affects GSC self-renewal and proliferation indicating that the HOP-PrPC complex is required for GSC stemness. Furthermore, PrPC-depleted GSCs downregulate cell adhesion-related proteins and impair cell migration indicating a putative role for PrPC in the cell surface stability of cell adhesion molecules and GBM cell invasiveness, respectively.ConclusionsIn conclusion, our results show that the modulation of HOP-PrPC engagement or the decrease of PrPC and HOP expression may represent a potential therapeutic intervention in GBM, regulating glioblastoma stem-like cell self-renewal, proliferation, and migration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0518-1) contains supplementary material, which is available to authorized users.

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“…It has been shown that the functions of extracellular HSPs can have both anti-tumour and pro-tumour effects, ranging from anti-tumour or pro-tumour immunomodulation (HSP90, HSP72, HSC70, HSP60, HSP27), through suppression or promotion of tumour cell proliferation (GRP78, HSP20, HSP27), to promotion of cancer cell invasion (HSP90, GRP75, HSP27) and angiogenesis (HSC70) [21][22][23][24][25][26]. Moreover, co-chaperones of HSP90, such as the HSP70/HSP90 organizing protein (HOP), HSP40 and p23, have also been shown to be extracellular, and similar to their role internal to the cell, are in complex with HSP90 to elicit extracellular functions such as MMP-2 activation and cancer cell invasion and migration [23,27].…”

Section: Intracellular Versus Extracellular Heat Shock Proteins In Camentioning

confidence: 99%

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

Edkins

Price

Pockley

et al. 2017

Phil. Trans. R. Soc. B

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Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’). Most importantly, these new insights are enlightening our understanding of biological processes in health and disease, and revealing novel and exciting therapeutic opportunities. This theme issue draws on therapeutic insights from established research on HSPs in cancer and other non-communicable disorders, with an emphasis on how the intracellular function of HSPs contrasts with their extracellular properties and function, and interrogates their potential diagnostic and therapeutic value to the prevention, management and treatment of chronic diseases. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

Cited by 55 publications

References 151 publications

Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells

Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

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