Abstract
Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell survival, especially in metastatic cancer progression. Epithelial–mesenchymal transition (EMT) plays an important role in metabolic rewiring of cancer cells as well as in phenotypic conversion and therapeutic resistance. Snail (SNAI1), a well-known inducer of cancer EMT, is critical in providing ATP and NADPH via suppression of several gatekeeper genes involving catabolic metabolism, such as phosphofructokinase 1 (PFK1), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase 2 (ACC2). Paradoxically, PFK1 and FBP1 are counter-opposing and rate-limiting reaction enzymes of glycolysis and gluconeogenesis, respectively. In this study, we report a distinct metabolic circuit of catabolic metabolism in breast cancer subtypes. Interestingly, PFKP and FBP1 are inversely correlated in clinical samples, indicating different metabolic subsets of breast cancer. The luminal types of breast cancer consist of the pentose phosphate pathway (PPP) subset by suppression of PFKP while the basal-like subtype (also known as triple negative breast cancer, TNBC) mainly utilizes glycolysis and mitochondrial fatty acid oxidation (FAO) by loss of FBP1 and ACC2. Notably, PPP remains active via upregulation of TIGAR in the FBP1-loss basal-like subset, indicating the importance of PPP in catabolic cancer metabolism. These results indicate different catabolic metabolic circuits and thus therapeutic strategies in breast cancer subsets.
Highlights
Malignant cancer cells continuously encounter altered environmental conditions of nutrient deficiency, hypoxia, and acidosis that challenge its survival
Analyzing TP53-induced glycolysis and apoptosis regulator (TIGAR) expression according to breast cancer subtypes, we found that TIGAR is increased in the FBP1-loss basal-like subtype of breast cancer (Figure 4)
These results suggest that phosphate pathway (PPP) is still important in triple negative breast cancers (TNBC) regardless of glycolysis and mitochondrial-dependent catabolic metabolism [74]
Summary
Malignant cancer cells continuously encounter altered environmental conditions of nutrient deficiency, hypoxia, and acidosis that challenge its survival. The ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH) are essential catabolic metabolites under starved environment, and are controlled by interconnected glycolysis, gluconeogenesis, pentose phosphate pathway (PPP), and mitochondrial activity such as fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycles (Figure 1). Snail abundance is inversely correlated [16,17,18] These Snail target genes are critical enzymes involving NADPH and ATP generation under glucose-starved environment, supporting the important role of Snail in catabolic metabolism during metastatic cancer progression. Metabolic interaction between PPP, FAO, and the glycolytic pathway via key enzyme regulation induces the overall carbon flux toward catabolism and promotes cell survival via ATP and NADPH production. 2,6-bisphosphate; TIGAR, TP53-induced glycolysis and apoptosis regulator; PFK, phosphofructokinase; FBP, fructose 1,6-bisphosphatase; F1,6BP, fructose 1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; AMK, AMP-activated protein kinase, ACC2, acetyl-CoA carboxylase 2; CPT1, carnitine palmitoyltransferase I; FAO, fatty acid oxidation; TCA, tricarboxylic acid
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