Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness

Eustace, Brenda K.; Sakurai, Takashi; Stewart, Jean K.; Yimlamai, Dean; Unger, Christine; Zehetmeier, Carol; Lain, Blanca; Torella, Claudia; Henning, Stefan; Beste, Gerald; Scroggins, Bradley T.; Neckers, Len; Ilag, Leodevico L.; Jay, Daniel G.

doi:10.1038/ncb1131

Cited by 551 publications

(527 citation statements)

References 41 publications

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“…Previously, secretion of HSP90a into the extracellular matrix surrounding tumour cells was reported to assist the activation of MMP-2 as well as contributing to tumour cell invasiveness [20,21]. We show that Hop is found in the conditioned medium of both Panc-1 and BxPc-3 cells and therefore may possibly have an extracellular role in Hsp90 client protein activation (Fig.…”

Section: Matrix Metalloproteinases Down Regulated As a Results Of Hop mentioning

confidence: 68%

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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Section: Matrix Metalloproteinases Down Regulated As a Results Of Hop mentioning

confidence: 68%

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

et al. 2011

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“…In this study, we revealed that vibsanin B preferentially targets HSP90b and has a very weak binding with HSP90a through activity-based protein profiling method (40), indicating that inhibition of HSP90b, but not HSP90a, would be mainly responsible for the inhibitory effect of vibsanin B on leukocyte migration. Because of high conservation in sequence, the function of HSP90a and HSP90b is very similar (41), although previous work reported that HSP90a, but not HSP90b, exerts an essential extracellular role in cancer cell invasiveness (42). At the level of structural biology, the HSP90 monomer contains three separate domains: the N-terminal domain, middle domain, and carboxyl-terminal domain, all of which bind different molecules to form functional HSP90 chaperone machinery (41).…”

Section: Discussionmentioning

confidence: 99%

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Deng

Shao

et al. 2015

The Journal of Immunology

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Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz–enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B’s effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

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“…Hsp70, Hsp90) are present in human plasma and CSF and are associated with cell surfaces (in particular cancer cells); they are thought to be released from dead or dying cells. Many potentially important extracellular roles have been proposed for these chaperones, such as cancer cell invasiveness (Eustace et al, 2004), immune presentation (Becker et al, 2002) and signaling (Whittall et al, 2006). However, these "normally intracellular" chaperones are present extracellularly at very low (ng/ml) levels and require ATP to carry out protein refolding.…”

Section: Extracellular Chaperonesmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness

Cited by 551 publications

References 41 publications

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

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

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Extracellular Chaperones and Amyloids

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