Metformin is a potential therapeutic for COVID-19/LUAD by regulating glucose metabolism

Abstract

Lung adenocarcinoma (LUAD) is the most common and aggressive subtype of lung cancer, and coronavirus disease 2019 (COVID-19) has become a serious public health threat worldwide. Patients with LUAD and COVID-19 have a poor prognosis. Therefore, finding medications that can be used to treat COVID-19/LUAD patients is essential. Bioinformatics analysis was used to identify 20 possible metformin target genes for the treatment of COVID-19/LUAD. PTEN and mTOR may serve as hub target genes of metformin. Metformin may be able to cure COVID-19/LUAD comorbidity through energy metabolism, oxidoreductase NADH activity, FoxO signalling pathway, AMPK signalling system, and mTOR signalling pathway, among other pathways, according to the results of bioinformatic research. Metformin has ability to inhibit the proliferation of A549 cells, according to the results of colony formation and proliferation assays. In A549 cells, metformin increased glucose uptake and lactate generation, while decreasing ATP synthesis and the NAD⁺/NADH ratio. In summary, PTEN and mTOR may be potential targets of metformin for the treatment of COVID-19/LUAD. The mechanism by which metformin inhibits lung adenocarcinoma cell proliferation may be related to glucose metabolism regulated by PI3K/AKT signalling and mTOR signalling pathways. Our study provides a new theoretical basis for the treatment of COVID-19/LUAD.

Keywords: Bioinformatics; COVID-19; Glucose metabolism; LUAD; Metformin.

Figure 1

Screening for DEGs from GEO datasets of COVID-19 and LUAD. The red and blue dots represented genes with increased or decreased expression in COVID-19 patients or LUAD patients, respectively, while the black dots represented genes with no significant difference in expression between COVID-19 or LUAD patients. (A) Volcano plot of DEGs in the GSE180226 dataset of COVID-19. (B) Volcano plot of DEGs in the GSE211378 dataset of COVID-19. (C) Volcano plot of DEGs in the GSE31210 dataset of LUAD. (D) Volcano plot of DEGs in the GSE75037 dataset of LUAD.

Figure 2

Screening the target genes of metformin for the treatment of COVID-19/LUAD. (A) Genes associated with COVID-19 from 2 GEO datasets and six databases. (B) Genes associated with LUAD from 2 GEO datasets, TCGA-LUAD dataset and five databases. (C) Target genes of metformin from five datasets. (D) The target genes of metformin for the treatment of LUAD/COVID-19.

Figure 3

Construction of PPI networks for target genes of metformin for the treatment of COVID-19/LUAD. (A) The PPI network was derived from the GeneMANIA database. The different relationships between nodes were indicated by the different colored connecting lines. Nodes were enriched in different functions indicated by the colors of the nodes. (B) PPI networks constructed from nodal degree values by Cytoscape software. The degree of the node was proportional to the depth of the node color.

Figure 4

GO and KEGG enrichment analysis of target genes of metformin for the treatment of COVID-19/LUAD. (A,C,E,G) The results of BP, CC, MF and KEGG term enrichment analysis, respectively. (B,D,F,H) The results of correlation analysis of BP, CC, MF and KEGG term enrichment analysis, respectively.

Figure 5

Top ten enrichment analysis results and corresponding genes. (A–D) The top ten results of BP, CC, MF and KEGG enrichment analysis and corresponding genes.

Figure 6

Effect of metformin on energy metabolism in LUAD. (A) The expression of PTEN, mTOR and PPARA in A549 cells treated with metformin in GSE146982 datasets. (B) Proliferation curves of A549 cells treated with 0 mM, 10 mM, 20 mM metformin, n = 3. (C) Clone formation of A549 cells treated with 0 mM, 10 mM, 20 mM metformin. (D) Glucose consumption and (E) lactate production of A549 cells treated with 0 mM, 2 mM, 4 mM, 10 mM metformin, n = 3. (F) ATP, (G) NAD⁺, (H) NADH and (I) NAD⁺/NADH of A549 cells treated with 0 mM, 10 mM, 20 mM metformin, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 7

Flowchart. This study follows this flowchart to explore the target genes and molecular mechanisms of metformin for the treatment of COVID-19/LUAD.