Figure 2

Regulation of glycolysis and fatty acid synthesis. The regulation of glycolysis and metabolism is far too complicated for one figure, but some of the key players described in the text are pictured. Akt promotes plasma membrane association of the glucose transporter, GLUT1, which transports glucose into the cell; it activates hexokinase (HK) association with the mitochondria; and it phosphorylates ATP citrate lyase (ACL), stimulating its activity of cleaving citrate to form oxaloacetate (OAA) and acetyl-coenzyme A (Ac-CoA), with downstream activation of fatty acid (FA) synthesis, which requires fatty acid synthase (FASN) and nicotinamide adenine dinucleotide phosphate (NADPH). Akt also inhibits fatty acid β-oxidation (β ox) via inhibition of carnitine palmitoyltransferase (CPT)1A, which imports fatty acids for mitochondrial β-oxidation. 2,4-Dienoyl-coenzyme A reductase (DecR1) is a β-oxidation enzyme, and its expression is often decreased in breast cancer. Impaired oxidative phosphorylation (Ox/Phos) leads to Akt activation. HK association with the mitochondria promotes phosphorylation of glucose to form glucose-6-phosphate, which can be metabolized via either glycolysis or the pentose phosphate pathway (PPP). Low levels of nutrients (such as high levels of AMP and low levels of ATP) cause activation of AMP-activated protein kinase (AMPK), which inhibits fatty acid synthesis and promotes fatty acid β-oxidation, and also phosphorylates/activates p53. p53 can inhibit glycolysis by inhibition of phosphoglycerate mutase (PGM) and can also arrest the cell cycle. However, p53 is commonly mutated in cancer cells, leading to a lack of cell cycle arrest and lack of PGM inhibition, as well as decreased expression of two p53 targets: TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome oxidase (SCO)2. This drives glycolysis by disfavoring oxidative phosphorylation and PPP. Hypoxia and/or oncogenes can activate hypoxia inducible factor (HIF), which can drive transcription of nearly all glycolysis-related enzymes (most not depicted), including pyruvate kinase (PK) and lactate dehydrogenase (LDH). Some oncogenes can activate PK and LDH independently of hypoxia and HIF.