Proteomic interrogation of HSP90 and insights for medical research

Weidenauer, Lorenz; Wang, Tai; Joshi, Suhasini; Chiosis, Gabriela; Quadroni, Manfredo

doi:10.1080/14789450.2017.1389649

Cited by 20 publications

(22 citation statements)

References 111 publications

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“…Cytosolic HSP90, with its large clientele of proteins, is a major network hub in the cellular proteome; as a result, pharmacological inhibition of HSP90 greatly destabilizes the cellular proteome [46][47][48][49][50][51]. This is in stark contrast to what we found for TRAP1, whose loss does not cause a significant imbalance in either the mitochondrial or cellular proteomes.…”

Section: Discussioncontrasting

confidence: 73%

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis

et al. 2020

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Background: The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other.Results: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far, the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline and an increase in OXPHOS. Conclusions: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

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Section: Discussioncontrasting

confidence: 73%

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis

et al. 2020

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“…As a common mechanism of action, HSPs are involved in various important cellular processes such as multiprotein assembly, secretion, trafficking, protein degradation, receptor maturation, signal transduction and regulation of transcription factors 21 , 22 . Heat shock protein 90 is a small family of 80–90 KDa chaperones, highly conserved across species and almost ubiquitously expressed, and is considered as the key regulator of proteostasis 23 , 24 . It is regarded as an ATP-dependent molecular chaperone, playing a key role in stabilising and activating > 200 client proteins.…”

Section: Introductionmentioning

confidence: 99%

“…It is regarded as an ATP-dependent molecular chaperone, playing a key role in stabilising and activating > 200 client proteins. It is divided into HSP90α (encoded by HSP90AA1) and HSP90β (encoded by HSP90AB1) [23][24][25] . HSP90 family is recognised as a suitable target for cancer therapy and is expected to actively elaborate in tumour cell proliferation, metastatic invasion, and death [21][22][23][24][25] .…”

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confidence: 99%

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

Anwar

Shalaby

Embaby

et al. 2020

Sci Rep

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Prodigiosin, a secondary metabolite red pigment produced by Serratia marcescens, has an interesting apoptotic efficacy against cancer cell lines with low or no toxicity on normal cells. HSP90α is known as a crucial and multimodal target in the treatment of TNBC. Our research attempts to assess the therapeutic potential of prodigiosin/PU-H71 combination on MDA-MB-231 cell line. The transcription and protein expression levels of different signalling pathways were assessed. Treatment of TNBC cells with both drugs resulted in a decrease of the number of adherent cells with apoptotic effects. Prodigiosin/PU-H71 combination increased the levels of caspases 3,8 and 9 and decreased the levels of mTOR expression. Additionally, there was a remarkable decrease of HSP90α transcription and expression levels upon treatment with combined therapy. Also, EGFR and VEGF expression levels decreased. This is the first study to show that prodigiosin/PU-H71 combination had potent cytotoxicity on MDA-MB-231 cells; proving to play a paramount role in interfering with key signalling pathways in TNBC. Interestingly, prodigiosin might be a potential anticancer agent to increase the sensitivity of TNBC cells to apoptosis. This study provides a new basis for upcoming studies to overcome drug resistance in TNBC cells.

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“…HS90B (Heat shock protein HSP 90-beta) is a molecular chaperone that promotes, along with its co-chaperones, the maturation, folding, and proper regulation of specific target proteins involved in cell cycle control, differentiation, gene expression, transcription factors, and signal transduction. [19] It was found to be Nglycosylated at the 96 arginine residue in control samples, while the lack of glycan was observed in MCF7 samples incubated with aptamers A26 and A33.…”

Section: Glycoproteome Changesmentioning

confidence: 93%

“…[19] It was found to be Nglycosylated at the 96 arginine residue in control samples, while the lack of glycan was observed in MCF7 samples incubated with aptamers A26 and A33. [19] It was found to be Nglycosylated at the 96 arginine residue in control samples, while the lack of glycan was observed in MCF7 samples incubated with aptamers A26 and A33.…”

mentioning

confidence: 93%

Changes in Protein Glycosylation as a Result of Aptamer Interactions with Cancer Cells

Drabik

Ner‐Kluza

Hartman

et al. 2019

Proteomics Clinical Apps

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Purpose Based on the recent aptamer‐related breast cancer studies, which indicate the therapeutic role of specific oligonucleotide sequences, experiments have been designed in an attempt to unravel the molecular targets of this mechanism. This article describes the study on glycoproteome changes in breast cancer cells as a result of their interactions with aptamers. Experimental design Aberrations in protein glycosylation play an important role in tumorigenesis and influence cancer progression, metastasis, immunoresponse, and chemoresistance, therefore this study is focused on the identification of the alterations in glycan expression on the surface of proteins as a potential and innovative tool for biomedical applications of aptamers in cancer treatment. Results Two proteins, kinesin‐like protein (KI13B) and proliferating cell nuclear antigen (PCNA), have been identified that carry N‐glycan epitopes after conjugation with aptamer sequences. Conclusions and clinical relevance Multiple features of aptamers as an alternative to protein antibodies are utilized for various biomedical applications ranging from biomarker discovery, bioimaging, targeted therapy, drug delivery, and drug pharmacokinetics and biodistribution. Frequently, aptamers bind to their target molecules and modulate their function. Such therapeutic aptamers can modify the biological pathways for treatment of many types of diseases, such as cancer.

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Proteomic interrogation of HSP90 and insights for medical research

Cited by 20 publications

References 111 publications

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis

Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights

Changes in Protein Glycosylation as a Result of Aptamer Interactions with Cancer Cells

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