Proteomics and phosphoproteomics of chordoma biopsies reveal alterations in multiple pathways and aberrant kinases activities

Abstract

BackgroundChordoma is a slow-growing but malignant subtype of bone sarcoma with relatively high recurrence rates and high resistance to chemotherapy. It is urgent to understand the underlying regulatory networks to determine more effective potential targets. Phosphorylative regulation is currently regarded as playing a significant role in tumorigenesis, and the use of tyrosine kinase inhibitors in clinical practice has yielded new promise for the treatment of a variety of sarcoma types.Materials and methodsWe performed comprehensive proteomic and phosphoproteomic analyses of chordoma using four-dimensional label-free liquid chromatography–tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. The potential aberrantly expressed kinases and their functions were validated using western blotting and CCK-8 assays.ResultsCompared with paired normal muscle tissues, 1,139 differentially expressed proteins (DEPs) and 776 differentially phosphorylated proteins (DPPs) were identified in chordoma tumor tissues. The developmentally significant Wnt-signaling pathway and oxidative phosphorylation were aberrant in chordoma. Moreover, we predicted three kinases (AURA, CDK9, and MOK) with elevated activity by kinase-pathway network analysis (KiPNA) and verified their increased expression levels. The knockdown of these kinases markedly suppressed chordoma cell growth, and this was also the case for cells treated with the CDK9 inhibitor AZD4573. We additionally examined 208 proteins whose expression and phosphorylation levels were synergetically altered.ConclusionsWe herein depicted the collective protein profiles of chordomas, providing insight into chordomagenesis and the potential development of new therapeutic targets.

Phosphoproteomics Profile of Chicken Cecum in the Response to Salmonella enterica Serovar Enteritidis Inoculation

“…Additionally, there has been little research to reveal the regulation mechanism of chicken cecum infected with S. Enteritidis in the phosphorylation levels of proteins. There has been a large amount of research on phosphorylated proteomics in human disease [21][22][23][24], bacteria [25], geese [26], goats [27,28], cattle [29], rats, and mice [30][31][32][33]. There were 62 phosphosites on 43 phosphoproteins which were determined to be up-regulated while 113 on 80 phosphoproteins were down-regulated in the research by Huang et al [34]; the up-regulated phosphoproteins were fewer than the down-regulated phosphoproteins.…”

Quantitative proteomic studies addressing unmet clinical needs in sarcoma

“…Hang et al. (2022) undertook proteomic and phosphoproteomic analyses to identify pathway alterations and aberrant kinase activity in chordoma ( 78 ). They demonstrated suppression of chordoma cell growth in functional experiments of identified proteins.…”