Lessons from Cancer Metabolism for Pulmonary Arterial Hypertension and Fibrosis

Abstract

Metabolism is essential for a living organism to sustain life. It provides energy to a cell by breaking down compounds (catabolism) and supplies building blocks for the synthesis of macromolecules (anabolism). Signal transduction pathways tightly regulate mammalian cellular metabolism. Simultaneously, metabolism itself serves as a signaling pathway to control many cellular processes, such as proliferation, differentiation, cell death, gene expression, and adaptation to stress. Considerable progress in the metabolism field has come from understanding how cancer cells co-opt metabolic pathways for growth and survival. Recent data also show that several metabolic pathways may participate in the pathogenesis of lung diseases, some of which could be promising therapeutic targets. In this translational review, we will outline the basic metabolic principles learned from the cancer metabolism field as they apply to the pathogenesis of pulmonary arterial hypertension and fibrosis and will place an emphasis on therapeutic potential.

Keywords: metabolism; metformin; pulmonary arterial hypertension; pulmonary fibrosis.

Figure 1.

Overview of intermediary metabolism. Upon changes in environmental conditions, cells respond by altering intermediary metabolism: the balance between AMPK-driven catabolism and mTORC1-driven anabolism. As a result of metabolism, H₂O₂ is generated that can control the cellular state and function. H₂O₂ can also have a detrimental consequence when it is converted into hydroxyl radicals (•OH) in the presence of ferrous iron (Fe^2 +) by the Fenton reaction. Subsequently, •OH in the presence of PUFAs can generate lipid hydroperoxides that can induce cell death known as ferroptosis. AMPK = AMP-activated protein kinase; mTORC1 = mTOR complex I; PUFA = polyunsaturated fatty acid; TCA = tricarboxylic acid.

Figure 2.

Metabolic heterogeneity among cancer cells. Most cancer cells exhibit robust flux through glycolysis and TCA cycle metabolism as well as their branched pathways. For tumor cells with mutations in TCA-cycle enzymes, tumor growth is still supported by alternative pathways such as glutamine-dependent reductive carboxylation or PC. αKG = α-ketoglutarate; ETC = electron transport chain; OAA = oxaloacetate; PC = pyruvate carboxylase; PDH = pyruvate dehydrogenase; PPP = pentose phosphate pathway.

Figure 3.

Metabolic intermediates as epigenetic regulators. TCA-cycle metabolites such as succinate, fumarate, and αKG control DNA and histone methylation by regulating αKG-dependent dioxygenases. D2HG, which is increased with mutations in IDH1 (isocitrate dehydrogenase 1) or IDH2, inhibits αKG-dependent dioxygenases. 1CM = one-carbon metabolism; ACLY = ATP-citrate lyase; D2HG = D-2-hydroxyglutarate; JMDH = Jumonji-c domain histone demethylase; SAM = S-adenosyl methionine; TET = ten–eleven translocation methylcytosine dioxygenase.

Figure 4.

Metabolic pathways involved in the pathology of pulmonary arterial hypertension (PAH). Dysregulated anabolism, characterized by enhanced glycolysis and TCA intermediates, is central to the pathogenesis of PAH. Targeting PDH in animal models showed promise for PAH therapy (DCA), indicating that suppressed PDH activity is important in PAH pathology. Cyt c = cytochrome c; DCA = dichloroacetate; e⁻ = electron; FAD = flavin adenine dinucleotide; FADH₂ = reduced form of FAD; Fructose-1,6-BP = fructose-1,6-bisphosphate; Glucose-6-P = glucose-6-phosphate; HIF-1 = hypoxia-inducible factor; PDK = PDH kinase; Ribose-5-P = ribose-5-phosphate.

Figure 5.

Signaling pathways that regulate the pathogenesis of pulmonary fibrosis. During the pathogenesis of idiopathic pulmonary fibrosis, TGF-β modulates metabolic signaling pathways by regulating redox signaling, enhancing serine and glycine synthesis by increased glucose influx, and promoting proline synthesis in mitochondria, which result in aberrant production of collagen. Fructose-2,6-BP = fructose-2,6-bisphosphate; Fructose-6-P = fructose-6-phosphate; G3P = glyceraldehyde 3-phosphate; GLS = glutaminase; GLUT1 = glucose transporter 1; GPX4 = glutathione peroxidase 4; NOX4 = NADP oxidase 4; P5CS = Δ¹‐pyrroline‐5‐carboxylate synthase; PFKFB3 = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PHGDH = phosphoglycerate dehydrogenase; PSAT1 = phosphoserine aminotransferase 1; PYCR1/2 = pyrroline‐5‐carboxylate reductase family member 1 or 2; SHMT = serine hydroxymethyltransferase; TGF-β = transforming growth factor-β.

Figure 6.

Cellular and molecular mechanisms of metformin. Oral metformin is absorbed in the GI tract and enters portal circulation to decrease hepatic glucose production. Improved hyperglycemia subsequently decreases circulating insulin levels and thus decreases the proliferation of insulin-responsive cells. On the other hand, metformin directly interacts with cells that express OCTs (organic cation transporters). Once metformin is transported into a cell via OCTs, it inhibits mitochondrial respiratory chain complex I. Mild inhibition of complex I induced by metformin results in an increase of the NADH/NAD⁺ ratio and reduced electron transfer. Consequently, cellular ATP levels decrease, and AMP accumulates, which leads to the activation of the AMPK signaling pathway. In addition, metformin limits the synthesis of aspartate and asparagine and thus inhibits cell proliferation (82). GI = gastrointestinal.