Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A small-molecule inhibitor targeting AKR1C1 suppresses cell proliferation and metastasis in non-small cell lung cancer

ABSTRACT: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, characterized by highly invasion and metastasis. Aldo-keto reductase family 1 member C1 (AKR1C1) plays an important role in cancer cell proliferation and metastasis and has gained attention as an anticancer drug target. Here we report that the natural sesquiterpene lactone alantolactone (ALA) was shown to bind directly to AKR1C1 through the Proteome Integral Solubility Alteration (PISA) analysis, a label-free target identification approach based on thermal proteome profiling.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Zhiwen FU

LAB HEAD: Zhiwen Fu

PROVIDER: PXD031082 | Pride | 2022-05-20

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	FA_1.raw	Raw
	FA_2.raw	Raw
	FB_1.raw	Raw
	checksum.txt	Txt
	txt.rar	Other

Items per page:

1 - 5 of 5

Publications

Natural Product Alantolactone Targeting AKR1C1 Suppresses Cell Proliferation and Metastasis in Non-Small-Cell Lung Cancer.

Fu Zhiwen Z Li Shijun S Liu Jinmei J Zhang Cong C Jian Chen C Wang Lulu L Zhang Yu Y Shi Chen C

Frontiers in pharmacology 20220315

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, characterized by high invasion and metastasis. Aldo-keto reductase family 1 member C1 (AKR1C1) plays an important role in cancer cell proliferation and metastasis, and has gained attention as an anticancer drug target. Here, we report that the natural sesquiterpene lactone alantolactone (ALA) was shown to bind directly to AKR1C1 through the Proteome Integral Solubility Alteration (PISA) analysis, a label-fr ...[more]

PMID: 35370661

Similar Datasets

Quantitative proteomics and RNA-sequencing of mouse liver endothelial cells identify novel regulators of BMP6 by iron

Project description:Iron induces hepcidin by activating bone morphogenetic protein (BMP)6-SMAD signaling. Liver endothelial cells (LECs) produce BMP6, but the molecular mechanisms are incompletely understood. To address this, we performed proteomics and RNA-sequencing on LECs from iron-adequate and iron-loaded mice. Gene set enrichment analysis identified transcription factors activated by high iron, including Nrf-2, which was previously reported to contribute to BMP6 regulation, and proto-oncogene c-Jun (encoded by Jun). Jun knockdown blocked Bmp6, but not Nrf-2 pathway, induction by iron in LEC cultures. Moreover, chromatin immunoprecipitation of mouse livers showed iron-dependent c-Jun binding to predicted sites in Bmp6 regulatory regions. Finally, c-Jun inhibitor blunted induction of Bmp6 and hepcidin, but not Nrf-2 activity, in iron-loaded mice. However, Bmp6 expression and iron parameters were unchanged in endothelial Jun knockout mice. Our data suggest that c-Jun participates in iron-mediated BMP6 regulation independent of Nrf-2, though the mechanisms may be redundant and/or multifactorial.

2023-12-28 | PXD039830 | Pride

Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells

Project description:4-Oxo-2-nonenal (ONE) derived from lipid peroxidation modifies nucleophiles and transduces redox signaling by its reactions with proteins. However, the molecular interactions between ONE and complex proteomes and their dynamics in situ remain largely unknown. Here we de-scribe a quantitative chemoproteomic analysis of protein adduction by ONE in cells, in which the cellular target profile of ONE is mimicked by its alkynyl surrogate. The analysis reveals four types of ONE-derived modifications in cells, including ketoamide and Schiff-base adducts to lysine, Michael adducts to cysteine, and a novel pyrrole adducts to cysteine. ONE-derived adducts co-localize and crosstalk with many histone marks and redox sensitive sites. All four types of modifications derived from ONE can be reversed site-specifically in cells. In summary, our study provides much-needed mechanistic insights into the cellular signaling and potential toxicities associated with this important lipid derived electrophile.

2022-02-24 | PXD006680 | Pride

A conserved tryptophan in the acylated segment controls β2- integrin-independent cell penetration of RTX toxins

Project description:The post-translationally acylated Repeats in ToXins (RTX) leukotoxins, such as the adenylate cyclase (CyaA) or α-hemolysin (HlyA), bind β2-integrins of leukocytes, but also penetrate cells lacking these receptors. We show that the indole of conserved tryptophans within the acylated segments, e.g. W876 in CyaA and W579 in HlyA, is crucial for β2-integrin-independent membrane penetration of toxins. Substitutions of W876 by aliphatic or aromatic residues did not affect acylation, folding or activities of CyaA W876L/F/Y toxin variants on CR3-expressing cells. In contrast, toxin activity of CyaA W876L/F/Y on cells lacking CR3 was strongly impaired. Similarly, a W579L substitution selectively reduced HlyA W579L cytotoxicity towards cells lacking β2-integrins. Intriguingly, the W876L/F/Y substitutions increased the thermal stability (Tm) of CyaA by 4 to 8 °C. In addition, the hydrogen-deuterium exchange revealed structural changes in the acylated segment of the CyaA W876F variant, compared to intact CyaA. The substitution of W876 with a polar glutamine (W876Q), not increasing the Tm, or combining of the W876F substitution with a cavity-filling V822M substitution, decreasing the Tm of CyaA W876F+V822M to a value closer to that of CyaA, yielded a milder defect of toxin activity on erythrocytes lacking CR3. Furthermore, the activity of CyaA was selectively impaired on erythrocytes when the interaction of the pyrrolidine of P848 with the indole of W876 was ablated. These results suggest that the bulky indole of the W876 of CyaA, or W579 of HlyA, rules the local structural flexibility of the acylated segment. This may facilitate adoption of a membrane-penetrating conformation of the toxins in the absence of β2-integrin-mediated positioning of the toxin towards the cell membrane.

2023-07-11 | PXD041207 | Pride

Mettl1-mediated B cell responses

Project description:Germinal center (GC) response requires increased protein synthesis. We identify the methyltransferase METTL1 as a translational checkpoint during GC responses. Therefore, we immunized mettl1-cko mice and control mice with NP-OVA, and sorted spleen B cells on day 14.

2024-11-01 | PXD057426 | Pride

The short isoform of the host antiviral protein ZAP acts as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting

Project description:Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. It allows production of essential viral structural and replicative enzymes that are encoded in an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshift elements and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the SARS-CoV-2 frameshift element and the host proteome. We reveal that the short isoform of the zinc-finger antiviral protein (ZAP-S) is a direct regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and inhibits viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and interferes with the folding of the frameshift RNA element. Together, these data identify ZAP-S as a host-encoded inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.

2021-11-25 | PXD029656 | Pride

TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting pro-survival autophagy

Project description:Bortezomib (bort) is an effective therapeutic agent for multiple myeloma (MM) patients; however, the majority of patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, while TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phospho-proteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated pro-survival autophagy. Our results provided that TRIM21 KD MM cell lines induced pro-survival autophagy after bort treatment, and suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of ATG5 restored bort sensitivity. Indeed, autophagy-related gene 5 (ATG5) expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the anti-myeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approaches.

2023-10-24 | PXD042004 | Pride

Mycobacterium smegtatis phosphoproteomics LC-MS/MS

Project description:Protein phosphatase PstP is conserved throughout the Actinobacteria in a genetic locus related to cell wall synthesis and cell division. In many Actinobacteria it is the sole annotated serine threonine protein phosphatase to counter the activity of multiple serine threonine protein kinases. We used transcriptional knockdown, electron microscopy and comparative phosphoproteomics to investigate the putative dual functions of PstP as a specific regulator of cell division and as a global regulator of protein phosphorylation. pstP knockdown in Mycobacterium smegmatis led to thickening of the cell wall and septum, changes in cell morphology, and eventual cell lysis. Comparative phosphoproteomics in the early stages of PstP depletion showed hyperphosphorylation of protein kinases and their substrates, confirming PstP as a negative regulator of kinase activity and global serine and threonine phosphorylation. Analysis of the 838 phosphorylation sites that changed significantly, suggested that PstP may have broad specificity, with preference for phosphothreonine, phosphosites near acidic residues, near the protein termini, and within membrane associated proteins. Increased phosphorylation of the activation loop of protein kinase B (PknB) and of the essential PknB substrate CwlM offer possible explanations for the essentiality of pstP and the cell wall defects when PstP was depleted.

2019-11-12 | PXD011805 | Pride

Deep proteomic and phosphoproteomic profiling of neuroblastoma treated with XPO1 inhibitor Selinexor

Project description:Neuroblastoma accounts for 15% of cancer-related deaths in children, highlighting an unmet need for novel therapies. Selinexor is a small molecule inhibitor of XPO1 that shuffles cargo proteins with a nuclear export sequence, many of which are essential for cancer growth and cell maintenance, from the nucleus to the cytosol. We systematically tested the effect of selinexor against neuroblastoma cells in vitro and in vivo and used a proteomics screening approach to interrogate unknown mechanisms of action. We found that selinexor induces its cytotoxic effects in neuroblastoma through the nuclear accumulation of p53. By combining selinexor with an aurora kinase inhibitor, alisertib that is already in clinical use for neuroblastoma, we show that p53-mediated lethality can be further augmented supporting clinical testing of this drug combination against neuroblastoma

2023-03-11 | PXD026454 | Pride

Two novel zinc and cobalt-responsive proteins in marine eukaryotic phytoplankton and implications for Zn scarcity in the surface oceans

Project description:Observations of scarce surface ocean concentrations of dissolved zinc (Zn) have raised the possibility that Zn may co-limit the growth of oceanic phytoplankton, yet testing this hypothesis has been difficult because Zn is highly prone to contamination. Biomarkers of micro-nutrient stress can serve as an alternate means to assay, though biomarker proteins for Zn stress in marine algae are currently uncharacterized. In this study we identified two Zn-responsive proteins in four marine diatom species that became abundant under Zn and Co limitation, but were scarce or undetectable in replete conditions. We refer to these proteins as ZCRP-A and ZCRP-B (Zn/Co Responsive Protein A and B). Sequence similarity of ZCRP-A to the Escherichia coli model COG0523 protein YjiA suggests a Zn2+ binding capability using conserved metal binding sites. Cellular localization by fluorescent tagging and overexpression of these proteins showed that ZCRP-B is part of a membrane-bound transport complex and that ZCRP-A serves as a Zn/Co chaperone with a chloroplastic target. These results imply that ZCRP-A and ZCRP-B are important in intracellular Zn trafficking and high-affinity transport, respectively. Metaproteomic detection of ZCRP-A and ZCRP-B homologs in a variety of eukaryotic protists along a South Pacific Ocean transect demonstrated that both proteins were more abundant in the euphotic zone (0-200m) where dZn and dCo were scarce. These findings describe widely distributed marine algal proteins linked to Zn and Co metabolism that together contribute to our understanding of Zn homeostasis in important marine phytoplankton.

2022-03-02 | PXD026953 | Pride

Detection of SEPs by MS - Unraveling the hidden universe of small proteins in bacterial genomes

Project description:Identifying smORFs and SEPs is technically and computationally challenging. Experimentally, techniques as ribosome profiling (Ribo-Seq and mass spectroscopy (MS) are used. Ribo-Seq sequences the mRNA and does not provide the translated frame, thus identifying proteins encoded by overlapping ORFs is not feasible. Herein we have used MS to characterize smORFomes of different Mycoplasma species. This data is used to corroborate the predictions of a random forest classifier that in silico predicts all the putative SEPs encoded by different bacterial genomes.

2019-03-01 | PXD008243 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data