LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

Figure 1

LKB1-proficient tumors display coordinated control of metabolism, DNA repair, and mitochondrial dynamics. LKB1 interacts with the pseudokinase STE20-Related Kinase Adaptor Alpha (STRADα) and with the armadillo-repeat containing protein MO25α. Once activated, LKB1 phosphorylates AMPK, which coordinates activation of catabolic processes—such as glycolysis, Krebs cycle, pentose phosphate pathway, fatty acid oxidation, and autophagy—and inhibition of anabolic processes—such as fatty acid synthesis and mTOR pathway. This maximizes ATP production and NADPH regeneration, thus controlling energy and redox homeostasis. Moreover, AMPK promotes mitochondrial fusion and mitophagy of damaged mitochondrial portions. In the nucleus, LKB1 fosters genomic integrity through sustaining homologous recombination. Black arrows from AMPK: direct phosphorylation. Red arrows: activation/upregulation. Yellow circles: phosphate groups. Red phospholipids in membranes: peroxidised phospholipids. Red stars in the nucleus: DNA damage sites. G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; F1,6BP: fructose 1,6-biphosphate; G3P: glyceraldehyde 3-phosphate; 1,3BPG: 1,3-biphosphoglycerate; 3PG: 3-phosphoglycerate; 2PG: 2-phosphoglycerate; PEP: phosphoenolpyruvate; Pyr: pyruvate; AcCoA: acetyl-coA; 6PG: 6-phosphogluconate; Ru5P: ribulose 5-phosphate; R5P: ribose 5-phosphate; GLUT: glucose transporter; GSH: reduced glutathione; GSSG: oxidized glutathione; H₂O₂: hydrogen peroxide; oxPPP: oxidative pentose phosphate pathway; TCA: tricarboxylic acid cycle; ETC: electron transport chain; FAO: fatty acid oxidation. The names of proteins deriving from disassembly of mTORC1 and NADPH oxidase complexes are omitted. See the text for details.