Integrated Metabolomics and Proteomics Highlight Altered Nicotinamide- and Polyamine Pathways in Lung Adenocarcinoma

Abstract

Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.

Keywords: Lung Adenocarcinoma; Metabolomics; Proteomics.

Figure 1.

Integrated networks of lung adenocarcinoma outlining biochemical relationships between metabolites, proteins and genes related to glycolysis and proximal biosynthetic pathways. Metabolites, proteins and genes are represented by circle, square and hexagonal, respectively. Node size indicates absolute magnitude of change. Node color shows the direction of changes comparing lung tumor and control tissues (red: increased in adenocarcinoma; green: decreased). Gray nodes represent features that were not detected. Significance is determined by yellow borders (pFDR < 0.05) or black borders (raw P < 0.05). Blue edges connect metabolites and proteins based on their enzymatic association. Purple edges link a protein and its encoding gene. Shaded areas represent the different biosynthetic pathways.

Figure 2.

Integrated networks of lung adenocarcinoma outlining biochemical pathways related to cysteine synthesis, glutathione synthesis and recycling and redox quenching. Metabolites, proteins and genes are represented by circle, square and hexagonal, respectively. Node size indicates absolute magnitude of change. Node color shows the direction of changes comparing lung tumor and control tissues (red: increased in adenocarcinoma; green: decreased). Gray nodes represent features that were not detected. Significance is determined by yellow borders (pFDR < 0.05) or black borders (raw P < 0.05). Blue edges connect metabolites and proteins based on their enzymatic association. Purple edges link a protein and its encoding gene. Shaded areas represent the different biosynthetic pathways.

Figure 3.

Integrated networks of lung adenocarcinoma depicting the relationship between NAD synthesis, one carbon metabolism and polyamine biosynthesis. Metabolites, proteins and genes are represented by circle, square and hexagonal respectively. Node size indicates absolute magnitude of change. Node color shows the direction of changes comparing lung tumor and control tissues (red: increased in adenocarcinoma; green: decreased). Gray nodes represent features that were not detected. Significance is determined by yellow borders (pFDR < 0.05) or black borders (raw P < 0.05). Blue edges connect metabolites and proteins based on their enzymatic association. Purple edges link a protein and its encoding gene. Shaded areas represent the different biosynthetic pathways.

Figure 4.

Integrated networks illustrating relationship between metabolites, proteins and genes related to pyrimidine metabolism, uracil catabolism and DNA repair. Metabolites, proteins and genes are represented by circle, square and hexagonal respectively. Node size indicates absolute magnitude of change. Node color shows the direction of changes comparing lung tumor and control tissues (red: increased in adenocarcinoma; green: decreased). Gray nodes represent features that were not detected. Significance is determined by yellow borders (pFDR < 0.05) or black borders (raw P < 0.05). Blue edges connect metabolites and proteins based on their enzymatic association. Purple edges link a protein and its encoding gene. Shaded areas represent the different biosynthetic pathways. Arrows indicate the direction of the respective enzymatic reaction.