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. 2009 Mar 1;23(5):537–548. doi: 10.1101/gad.1756509

Figure 1.

Figure 1.

Metabolic pathways of growth and proliferation. Growth factor-independent activation of the PI3K/Akt and c-Myc pathways drives changes in cellular metabolism to promote cancer cell growth and proliferation. PI3K/Akt and c-Myc facilitate increased rates of glucose uptake and glycolysis. Lactate dehydrogenase (LDH-A) maintains glycolytic flux by converting excess pyruvate to lactate and regenerating NAD+ in the process. Akt signaling promotes increased surface expression of the glucose transporter Glut1 and enhances the activity of glycolytic enzymes. Glucose (Glc) has multiple catabolic and biosynthetic fates, including glycolytic processing for production of ATP and pyruvate, processing through the pentose phosphate shunt to generate ribose 5-phosphate (Rib-5-P) and NADPH for nucleotide biosynthesis, or entry into the mitochondrion for biosynthesis or ATP generation by the TCA cycle and electron transport chain (ETC). Glucose-derived citrate (Cit) is exported to the cytosol and processed by ATP citrate lyase (ACL) to acetyl-CoA (Ac-CoA), which is channeled into lipid production. Glutamine (Gln) is deaminated to form glutamate, which can be processed further in the mitochondria by glutamate dehydrogenase (GDH) to generate α-ketoglutarate (αKG) and maintain TCA cycle function. Reactive oxygen species (ROS) are the result of mitochondrial OXPHOS. The TORC1 complex, which contains mTOR and its binding partner Raptor, regulates protein translation. mTOR coordinates surface expression of amino acid (AA) transporters, and promotes translation initiation by stimulating ribosomal S6 kinase activity and relieving 4E-BP-mediated inhibition of eIF4E. Amino acids stimulate mTOR activity through the activity of the Rag GTPases. PI3K/Akt signals activate mTOR primarily through inhibition of the TSC1–TSC2 complex, thus releasing inhibition of RhebGTP and activating mTOR. Bioenergetic signals antagonize the TORC1 complex through the LKB1–AMPK pathway. Known oncogenes are shown in green, tumor suppressors in red, and effectors with undefined roles in tumorigenesis are shown in blue.