Untargeted lipidomic analysis and network pharmacology for parthenolide treated papillary thyroid carcinoma cells

Abstract

Background: With fast rising incidence, papillary thyroid carcinoma (PTC) is the most common head and neck cancer. Parthenolide, isolated from traditional Chinese medicine, inhibits various cancer cells, including PTC cells. The aim was to investigate the lipid profile and lipid changes of PTC cells when treated with parthenolide.

Methods: Comprehensive lipidomic analysis of parthenolide treated PTC cells was conducted using a UHPLC/Q-TOF-MS platform, and the changed lipid profile and specific altered lipid species were explored. Network pharmacology and molecular docking were performed to show the associations among parthenolide, changed lipid species, and potential target genes.

Results: With high stability and reproducibility, a total of 34 lipid classes and 1736 lipid species were identified. Lipid class analysis indicated that parthenolide treated PTC cells contained higher levels of fatty acid (FA), cholesterol ester (ChE), simple glc series 3 (CerG3) and lysophosphatidylglycerol (LPG), lower levels of zymosterol (ZyE) and Monogalactosyldiacylglycerol (MGDG) than controlled ones, but with no significant differences. Several specific lipid species were changed significantly in PTC cells treated by parthenolide, including the increasing of phosphatidylcholine (PC) (12:0e/16:0), PC (18:0/20:4), CerG3 (d18:1/24:1), lysophosphatidylethanolamine (LPE) (18:0), phosphatidylinositol (PI) (19:0/20:4), lysophosphatidylcholine (LPC) (28:0), ChE (22:6), and the decreasing of phosphatidylethanolamine (PE) (16:1/17:0), PC (34:1) and PC (16:0p/18:0). Four key targets (PLA2G4A, LCAT, LRAT, and PLA2G2A) were discovered when combining network pharmacology and lipidomics. Among them, PLA2G2A and PLA2G4A were able to bind with parthenolide confirmed by molecular docking.

Conclusions: The changed lipid profile and several significantly altered lipid species of parthenolide treated PTC cells were observed. These altered lipid species, such as PC (34:1), and PC (16:0p/18:0), may be involved in the antitumor mechanisms of parthenolide. PLA2G2A and PLA2G4A may play key roles when parthenolide treated PTC cells.

Keywords: Lipidomics; Network pharmacology; Parthenolide; Phosphatidylcholine; Thyroid cancer.

Fig. 1

The lipid class and number identified in this study

Fig. 2

Parthenolide (T) altered the abundance of lipid class in papillary thyroid cells compared with control group (C), but with no significance. All P > 0.05. FA, fatty acid; ChE, cholesterol ester; CerG3, simple glc series 3; LPG, lysophosphatidylglycerol; ZyE, zymosterol; MGDG, monogalactosyldiacylglycerol

Fig. 3

A Visible separation was not identified clearly between the two groups from the score plot of principal component analysis (PCA). B Partial least-squares determinant analysis (PLS-DA) showed a complete separation of detected ions in parthenolide treated groups from control groups [R2X (cum) = 0.384, R2Y (cum) = 0.907, Q2 (cum) = 0.44]. C Orthogonal projections to latent structures discriminant analysis (OPLS-DA) showed a complete separation of detected ions in parthenolide treated groups from control groups [R2X (cum) = 0.384, R2Y (cum) = 0.907, Q2 (cum) = 0.509]. D Permutation test of the PLS-DA model [Q2-intercept = -0.7946]. E Permutation test of the OPLS-DA model [Q2-intercept = -0.3653]

Fig. 4

A The volcano plot of lipid species between the two groups based on the results of univariate analysis (fold change (FC) > 1.5 or FC < 0.67, P-value < 0. 05 and VIP > 1). B Hierarchical clustering of the 10 significantly changed lipid species. C The correlation analysis shows the correlation between the significant lipid species

Fig. 5

The protein–protein interaction networks by STRING. White nodes: lipid metabolite targets. Yellow nodes: potential parthenolide targets; Red node (PLA2G2A): both lipid metabolite and potential parthenolide targets

Fig. 6

The compound-target-metabolite network of parthenolide treated papillary thyroid carcinoma cells. (Red: Compound, Blue: predicted-targets, Green: lipid metabolite targets, Yellow: lipid metabolites)

Fig. 7

The binding mode of parthenolide and PLA2G2A (A) and PLA2G4A (B)