fig 3 (IMAGE)
Caption
PIK3CA mutations reprogram cancer metabolism. PI3K activation renders cancer cells dependent on glutamine metabolism through the AKT-independent PDK1-RSK2-ATF4 axis. Transcript factor ATF4 increases the expression of GPT2, accelerating conversion from glutamate to α-KG in mitochondria. α-KG then goes into the tricarboxylic acid (TCA) cycle and fuels the cancer cell. PI3K activation evaluates the ability to use glucose as a fuel through multiple effectors. PI3K increases the pumping of glucose through the up-regulating expression of glucose transporter GLUT1 by HIF1α. Meanwhile, PI3K blocked endocytosis of GLUT1 by inhibiting TXNIP, maintaining GLUT1 on cell membranes. AKT activates HK2, which converts glucose to cell membrane impenetrable glucose-6-phosphate and accumulates glucose-6-phosphate in the cytoplasm for ATP production. AKT promotes another important reaction by activating PFKFB2 to produce a potent allosteric activator of PFK1. α-KG, alpha-ketoglutarate; AKT, protein kinase B; ATF4, activating transcription factor 4; GLS1, kidney-type glutaminase; GLS2, liver-type glutaminase; GLUT1, glucose transporter 1; GPT2, glutamate pyruvate transaminase 2; HIF1α, hypoxia-inducible factor 1α; HK2, hexokinase 2; PDK1, phosphoinositide-dependent kinase 1; PFK1, phosphofructokinase 1; PFKFB2, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PI3K, phosphoinositide 3-kinase; RSK2, ribosomal s6 kinase 2; TXNIP, thioredoxin-interacting protein.
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