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HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

ABSTRACT: Two human primary fibroblast cell lines indicated in the file names were either treated with carfilzomib (C) at the concentrations near the IC50 of proteasome activity (10nM) for 24h, or with DMSO (D) as a control, in biological duplicates (numbers 1-2).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Jacek Wisniewski

LAB HEAD: Jacek R. Wisniewski

PROVIDER: PXD027840 | Pride | 2025-10-29

REPOSITORIES: Pride

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			Action	DRS
	20201014_EXPL1_JRW_SA_L_XX1.raw	Raw
	20201014_EXPL1_JRW_SA_L_XX10.raw	Raw
	20201014_EXPL1_JRW_SA_L_XX2.raw	Raw
	20201014_EXPL1_JRW_SA_L_XX3.raw	Raw
	20201014_EXPL1_JRW_SA_L_XX4.raw	Raw

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HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

Project description:Cell lines indicated in the file names were either treated with carfilzomib (C) at concentrations near the IC50 of proteasome activity in each cell line for 24h, or with DMSO (D) as a control, in biological duplicates.

2025-10-29 | PXD025364 | Pride

HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

Project description:In this study we employed a label-free global proteomics approach, with a sensitivity of over 10k quantified proteins per sample, to determine contributions of different compensatory mechanisms upon the proteasome inhibition with carfilzomib - in cells of multiple myeloma, normal fibroblasts and cancers of lung, colon and pancreas. We identified several responding pathways, while the main HSP70 family stress inducible molecular chaperones HSPA1A and HSPA1B (often addressed jointly as HSPA1A/B or simply “Hsp70”, due to nearly identical protein sequences) were the most universal proteasome inhibition responders in proteomes of all the studied cell types. Further overlap of differential proteomics with RNA-seq analysis obtained at the same condions (DMSO control vs carfilzomib treatment) and a subsequent validation showed that the proteasome inhibition-dependent induction of HSPA1A/B and other chaperone proteins in cancer cells is in fact transcription-driven.

2022-09-22 | GSE184029 | GEO

Proteomic-based analysis of hypoxia and physioxia responsive proteins and pathways in DLBCLProteomic-based analysis of hypoxia and physioxia responsive proteins and pathways in DLBCL

Project description:Hypoxia is damaging to normal cells as well as cancerous cells. Reports assessing hypoxia- and physioxia-induced global proteome changes in lymphoma are lacking. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to the acute hypoxic stress (1% of O2) and the physioxia (5% of O2) for a long-time. A total of 8239 proteins were identified by LC-MS/MS, of which 718, 513, and 486 have significant changes in abundance in Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant down-regulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, down-regulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of up-regulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a varia-ble oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL, potentially important in developing more aggressive phenotype.

2022-02-17 | PXD026726 | Pride

Human liver cells proteome

Project description:The human liver functions through a complex interplay of parenchymal and non-parenchymal cells, which participate in performing many essential aspects of metabolism and secretion. Mass spectrometry-based proteomic analysis of intact tissue has improved the understanding of these processes, by providing an in-depth view of the human liver proteome. However, the predominance of parenchymal cells, i.e. hepatocytes, means that the total tissue proteome mainly reflects hepatocyte expression. In this study, we therefore used quantitative label-free proteomic analysis to analyze the proteomes of the major parenchymal and non-parenchymal cell types in the human liver, i.e. hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. We found that our data recapitulated specific functional differences between cell types, meaning that it can be used to reliably probe various aspects of cellular interplay. Thus, the data we provide constitutes a unique resource for exploring the human liver proteome at major cell type resolution.

2020-04-09 | PXD012615 | Pride

Comparison of proteome composition of serum enriched in extracellular vesicles isolated from polycythemia vera patients and healthy controls

Project description:Extracellular vesicles (EVs), e.g., exosomes and microvesicles, are one of the main networks of intercellular communication. In myeloproliferative disorders, such as polycythemia vera (PV), excess of EVs originating from overabundant blood cells can directly contribute to thrombosis through their procoagulant activity. However, proteomic composition of these vesicles in PV patients has not been investigated before. In this work, we examined proteomic composition of serum exosomes of PV patients in comparison to healthy controls. We processed exosome-enriched serum samples using Multiple Enzyme Filter Aided Sample Preparation approach (MED-FASP), conducted LC-MS/MS measurements on a Q-Exactive HF-X mass spectrometer, and quantitatively analyzed the absolute concentrations of identified proteins by Total Protein Approach (TPA). 38 proteins were present at statistically significant different concentrations between PV patients’ study group and healthy controls’ group. The main protein components deregulated in PV were primarily related with excessive amounts of cells (TFRC, SELL, GP5), increased platelet activation (SERPINE1, MMRN1), elevated immune and inflammatory response (HPSE, CAMP, LYZ, SELL, LTF), and high concentrations of procoagulant and angiogenetic agents (ANG, HPSE). Our study provides the first quantitative analysis of the serum exosomes’ proteome in PV patients. Acquired knowledge can be beneficial to understanding of the mechanism of PV disease and further development of diagnostic or therapeutic procedures.

2019-05-13 | PXD013234 | Pride

Regulation of Megakaryocytic differentiation in Cell Line Models by Dynamic Combinatorial Interactions of RUNX1 with Its Cooperating Partners

Project description:Regulation of Megakaryocytic differentiation in Cell Line Models by Dynamic Combinatorial Interactions of RUNX1 with Its Cooperating Partners Examination of RUNX1 binding in K562 cells, before and following TPA induction and CMK cells. Examination of GATA1 and FOS binding and H3K4me1 and H3K27me3 modification levels following TPA induction in K562 cells.

2011-01-10 | E-GEOD-24777 | biostudies-arrayexpress

Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models

Project description:This SuperSeries is composed of the following subset Series: GSE24777: Regulation of Megakaryocytic differentiation in Cell Line Models by Dynamic Combinatorial Interactions of RUNX1 with Its Cooperating Partners GSE24778: Expresssion data in K562 cells, before and after TPA induction and including a RUNX1 knockout construct or a control structure Refer to individual Series

2011-01-10 | E-GEOD-24779 | biostudies-arrayexpress

Global quantitative proteomics of mouse brain structures reveals significant alterations in expression of proteins involved in neuronal plasticity during aging

Project description:Aging is believed to be the result of alterations of protein expression and accumulation of changes in biomolecules. Although there are numerous reports demonstrating changes in protein expression in brain during aging, only few of them describe global changes in the protein level. Here, we present a deepest quantitative proteomic analysis of three brain regions, hippocampus, cortex and cerebellum, in mice aged 1 and 12 months, using the total protein approach technique. In all the brain regions, both in young and in middle-aged animals, we identified over 6,700 proteins. We found that although the total protein expression in middle-aged brain structures is practically unaffected by aging, there are significant differences between young adult and middle-aged mice in the expression of some receptors and signaling cascade proteins proven to be significant for learning and memory formation. Our analysis demonstrates that hippocampus is the most unstable structure during natural aging and that the first symptoms of weakening of neuronal plasticity may be observed on protein level in middle-aged animals.

2018-07-03 | PXD009792 | Pride

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

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