Identification of Celecoxib-Targeted Proteins Using Label-Free Thermal Proteome Profiling on Rat Hippocampus

Gholizadeh, Elham; Karbalaei, Reza; Khaleghian, Ali; Salimi, Mona; Gilany, Kambiz; Soliymani, Rabah; Tanoli, Ziaurrehman; Rezadoost, Hassan; Baumann, Marc; Jafari, Mohieddin; Tang, Jing

doi:10.1124/molpharm.120.000210

Cited by 11 publications

(12 citation statements)

References 101 publications

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“…It should be noted that for cancer drugs, focusing on primary targets still induce a risk of missing additional targets that account for the treatment effecacy 1,39 . In the future, we expect that the proteome-wide drug target binding experiments could generate more unbiased data to improve computational prediction methods for drug target prediction 8,40 .…”

Section: Discussionmentioning

confidence: 99%

A gene essentiality signature enables predicting the mechanism of action of drugs

Wang

Bao

Zheng

et al. 2022

Preprint

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BackgroundCancer drugs often kill cells independent of their putative targets, suggesting the limitation of existing drug target information. The lack of understanding of a drug’s mechanism of action may prevent biomarker identification and ultimately lead to attrition in clinical trials. Current experimental strategies, such as binding affinity assays provide limited coverage at the proteome scale. In this study, we explored whether the integration of loss-of-function genetic and drug sensitivity screening data could define a novel signature to better understand the mechanisms of action of drugs.MethodsLoss-of-function genetic screening data was collected from the DepMap database, while drug sensitivity data were collected from three extensive screening studies, namely CTRP (n = 545), GDSC (n = 198), and PRISM (n = 1448). An L1 penalized regression model using the gene essentiality features was constructed for each drug to predict its sensitivity on multiple cell lines. The optimized model coefficients were then considered as the gene essentiality signature of the drug. We compared the gene essentiality signature with structure-based fingerprints and the gene expression signature of cancer drugs in predictions of their known targets. Finally, we applied the gene essentiality signature to predict the novel targets for a panel of noncancer drugs with potential anticancer efficacy.ResultsWe showed that the gene essentiality signature can predict drug targets and their downstream signaling pathways. Both supervised and unsupervised prediction accuracies were higher than those using chemical fingerprints and gene expression signatures. Pathway analyses of these gene essentiality signatures confirmed key mechanisms previously reported, including the EGFR signaling network for lapatinib, and DNA mismatch repair drugs. Finally, we showed that the gene essentiality signature of noncancer drugs can discover novel targets.ConclusionsIntegrating drug sensitivity data and loss-of-function genetic data enables the construction of gene essentiality signatures that help discover drug targets and their downstream signaling pathways. We found novel targets for noncancer drugs that explain their anticancer efficacy, paving the way for the rational design of drug repurposing.

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Section: Discussionmentioning

confidence: 99%

A gene essentiality signature enables predicting the mechanism of action of drugs

Wang

Bao

Zheng

et al. 2022

Preprint

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“…Typtic digests were analyzed in nano‐LC‐Thermo Q Exactive Plus Orbi‐Trap MS as described by us before (Gholizadeh et al , 2021 ). 1 µg of peptides in each biological sample was separated by Easy‐nLC system (Thermo Scientific) equipped with a reverse‐phase trapping column Acclaim PepMapTM 100 (C18, 75 μm × 20 mm, 3‐μm particles, 100 Å; Thermo Scientific), followed by an analytical Acclaim PepMapTM 100 RSLC reversed‐phase column (C18, 75 µm × 250 mm, 2‐µm particles, 100 Å; Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

Isotope‐labeled amyloid‐β does not transmit to the brain in a prion‐like manner after peripheral administration

et al. 2022

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Findings of early cerebral amyloid-b deposition in mice after peripheral injection of amyloid-b-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-b aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that Ab actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate 13 C-isotope-labeled brain extracts from mice expressing human amyloid-b and track 13 C-lysine-labeled amyloid-b after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-b in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13 C-lysine-labeled amyloid-b is not detectable in the brain whereas the mice incorporate 13 C-lysine from the donor brain extracts into endogenous amyloid-b. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-b does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer's disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.

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“…For plasma, the suitability of a targeted proteomics approach with a set of several hundreds of proteins, via application of a cutting-edge multiple reaction monitoring (MRM) and labeled peptide counterparts, is carefully assessed [ 145 ]. For the snap-frozen RAA tissues, an untargeted label-free mass spectrometry approach is primarily preferred [ 115 , 146 ].…”

Section: Methodsmentioning

confidence: 99%

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Sikorski

Karjalainen

Blokhina

et al. 2021

IJMS

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Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

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Identification of Celecoxib-Targeted Proteins Using Label-Free Thermal Proteome Profiling on Rat Hippocampus

Cited by 11 publications

References 101 publications

A gene essentiality signature enables predicting the mechanism of action of drugs

A gene essentiality signature enables predicting the mechanism of action of drugs

Isotope‐labeled amyloid‐β does not transmit to the brain in a prion‐like manner after peripheral administration

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

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