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Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes

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Abstract

Protein tyrosine nitration is a selectively and reversible important post-translational modification, which is closely related to oxidative stress. Astrocytoma is the most common neuroepithelial tumor with heterogeneity and complexity. In the past, the diagnosis of astrocytoma was based on the histological and clinical features, and the treatment methods were nothing more than surgery-assisted radiotherapy and chemotherapy. Obviously, traditional methods short falls an effective treatment for astrocytoma. In late 2021, the World Health Organization (WHO) adopted molecular biomarkers in the comprehensive diagnosis of astrocytoma, such as IDH-mutant and DNA methylation, which enabled the risk stratification, classification, and clinical prognosis prediction of astrocytoma to be more correct. Protein tyrosine nitration is closely related to the pathogenesis of astrocytoma. We hypothesize that nitroproteome is significantly different in astrocytoma relative to controls, which leads to establishment of nitroprotein biomarkers for patient stratification, diagnostics, and prediction of disease stages and severity grade, targeted prevention in secondary care, treatment algorithms tailored to individualized patient profile in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Nitroproteomics based on gel electrophoresis and tandem mass spectrometry is an effective tool to identify the nitroproteins and effective biomarkers in human astrocytomas, clarifying the biological roles of oxidative/nitrative stress in the pathophysiology of astrocytomas, functional characteristics of nitroproteins in astrocytomas, nitration-mediated signal pathway network, and early diagnosis and treatment of astrocytomas. The results finds that these nitroproteins are enriched in mitotic cell components, which are related to transcription regulation, signal transduction, controlling subcellular organelle events, cell perception, maintaining cell homeostasis, and immune activity. Eleven statistically significant signal pathways are identified in astrocytoma, including remodeling of epithelial adherens junctions, germ cell-sertoli cell junction signaling, 14-3-3-mediated signaling, phagosome maturation, gap junction signaling, axonal guidance signaling, assembly of RNA polymerase III complex, and TREM1 signaling. Furthermore, protein tyrosine nitration is closely associated with the therapeutic effects of protein drugs, and molecular mechanism and drug targets of cancer. It provides valuable data for studying the protein nitration biomarkers, molecular mechanisms, and therapeutic targets of astrocytoma towards PPPM (3P medicine) practice.

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Abbreviations

3-NT :

3-nitrotyrosine

3-AT :

3-aminotyrosine

2DGE :

two-dimensional gel electrophoresis

Bcl-2 :

B cell lymphoma-2

Bak :

BCL2 antagonist/killer

BSA :

bovine serum albumin

CNS :

central nervous system

CID :

collision-induced dissociation

CCs :

cell components

eNOS :

endothelial nitric oxide synthase

ESI :

electrospray ionization

ECD :

electron-capture dissociation

ETD :

electron-transfer dissociation

FAD :

Food and Drug Administration

GAPDH :

glyceraldehyde-3-phosphate dehydrogenase

GO :

Gene Ontology

GBM :

glioblastoma

H2O2 :

hydrogen peroxide

H 2 S :

hydrogen sulfide

HPLC :

high-performance liquid chromatography

iTRAQ :

isobaric tag for relative absolute quantification

iNOS :

inducible form of nitric oxide synthase

IPA :

ingenuity canonical pathways

LC :

liquid chromatography

LPO :

lactoperoxidase

MS :

mass spectrometry

MS/MS :

tandem mass spectrometry

MALDI-TOF :

matrix-assisted laser desorption/ionization time-of-flight

MAPK :

mitogen-activated protein kinases

MnSOD :

manganese superoxide dismutase

MAD :

metastable atom-activated dissociation

MFs :

molecular functions

NO :

nitric oxide

NO 2 :

nitrogen dioxide

NOX2 :

nicotinamide adenine dinucleotide phosphate oxidase 2

NOS :

nitric oxide synthases

nNOS :

neuronal nitric oxide synthase

Nrf2 :

nuclear factor E2-related factor 2

NF-κB :

nuclear factor-kappaB

ONOO − :

peroxynitrite

PRR :

pattern recognition receptor activity

RNS :

reactive nitrogen species

ROS :

reactive oxygen species

STAT1 :

signal transducer and activator of transcription 1

TCoB :

tubulin cofactor B

TCR :

T cell receptor

TMT :

tandem mass tags

TUBB :

nitrified tubulin β class I gene

UV :

ultraviolet

WHO :

World Health Organization

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This work was supported by the Shandong Provincial Taishan Scholar Engineering Project Special Funds (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR2021MH156; ZR2022QH112), the Shandong First Medical University Talent Introduction Funds (to X.Z.), the Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), China National Nature Scientific Funds (81272798 to X.Z.; 82203592 to N.L.).

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  1. Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China

    Wenshuang Jia, Xiaoxia Gong, Zhen Ye, Na Li & Xianquan Zhan

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  2. Xiaoxia Gong
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W.J. collected and analyzed literature, and wrote the manuscript. X.G., Z.Y., and N.L. participated in the data analysis. X.Z. conceived the concept, designed the manuscript, coordinated, wrote and critically revised manuscript, and was responsible for its financial supports and the corresponding works. All authors approved the final manuscript.

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Jia, W., Gong, X., Ye, Z. et al. Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes. EPMA Journal 14, 673–696 (2023). https://doi.org/10.1007/s13167-023-00348-y

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