Fig. 3

TGF-β-dependent metabolism reprogramming of cancer cells. 1. For glucose metabolism, TGF-β signaling can: a. enhance glycolysis by directly increasing the glycolytic enzyme expression of PKM2 and LDH, and indirectly elevate the PFKFB3, which augments the expression of PFK1, one of the glycolytic enzymes; b. TCA cycle enzyme SDH mutation leads to TGF-β-induced EMT; c. augment PPP by increasing G6PD, the first key enzyme of PPP; and d. promote glycogen synthesis by boosting GYS1 expression via inhibiting GSK-3 that deactivates GYS1. 2. For cholesterol metabolism, a. cholesterol-enriched subdomain-mediated TGF-β receptor endocytosis can: destruct TGF-β receptors that abrogate TGF-β signaling initiation; b. cholesterol synthesis enzyme NSDHL can inhibit TGF-β1 production and attenuate TGF-β signaling; c. NSDHL also prevents TGF-βRII endocytosis and then facilitates TGF-β signaling; and d. TGF-β signaling can decrease cholesterol synthesis by inactivating SREBF2, a cholesterol synthesis promoter. 3. For fatty acid metabolism, a. canonical (p-SMAD2) and non-canonical (p-AMPK) TGF-β signaling accelerates FAO; b. TGF-β1 can increase FASN expression, thus allowing fatty acid synthesis and accumulation in cancer cells; conversely, FASN enhances TGF-β1 production. Moreover, non-canonical (p-AMPK) signaling decreases FASN; c. TGF-β2 releasement by the acidic TMME enables more fatty acid entry into cancer cells and forms LD for lipid storage used by FAO. 4. For amino acid metabolism, TGF-β signaling can: a. increase Asp, Glu, and Lys, while decrease Ala, Asn, Gln, etc.; b. bolster glutamine’s entry into cancer cells by elevating SLC7A5, and enhance glutamine’s catalyzation into glutamate via increasing GLS1, and glutamate can flow into TCA cycle. Green highlighted items mean TGF-β signaling positively regulates them, or they are positively regulated by TGF-β signaling. Red vice versa. And these green and red ones are potentially TGF-β-dependent metabolic targets in cancer. HK2: Hexokinase 2; G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; PFK1: phosphofructokinase 1; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PPP: pentose phosphate pathway; Acetyl-CoA: acetyl coenzyme A; GYS1: glycogen synthase 1; GSK-3: glycogen synthase kinase 3; F-1,6-P: fructose-1,6-bisphosphate; G3P: glyceraldehyde 3-phosphate; PEP: phosphoenolpyruvate; PKM2: pyruvate kinase M2; LDH: Lactate dehydrogenase; SREBF2: sterol regulatory element-binding transcription factor 2; FASN: fatty acid synthase; FAO: fatty acid oxidation; LD: lipid droplet. ASP: aspartic acid; Glu: glutamic acid; Lys: lysine; Ala: alanine; Asn: asparagine; Gln: glutamine; Gly: glycine; His: histidine; Ile: isoleucine; Leu: leucine; Phe: phenylalanine; Pro: proline; Thr: threonine; Tyr: tyrosine. SLC7A5: glutamine transporter solute carrier family 7 member 5; and GLS1: glutaminase 1