Unravelling the connection between metabolism and tumorigenesis through studies of the liver kinase B1 tumour suppressor

Abstract

The liver kinase B1 (LKB1) tumour suppressor functions as a master regulator of growth, metabolism and survival in cells, which is frequently mutated in sporadic human non-small cell lung and cervical cancers. LKB1 functions as a key upstream activator of the AMP-activated protein kinase (AMPK), a central metabolic switch found in all eukaryotes that govern glucose and lipid metabolism and autophagy in response to alterations in nutrients and intracellular energy levels. The LKB1/AMPK signalling pathway suppresses mammalian target of rapamycin complex 1 (mTORC1), an essential regulator of cell growth in all eukaryotes that is deregulated in a majority of human cancers. LKB1 inactivation in cancer leads to both tumorigenesis and metabolic deregulation through the AMPK and mTORC1-signalling axis and there remain critical challenges to elucidate the direct role LKB1 inactivation plays in driving aberrant metabolism and tumour growth. This review addresses past and current efforts to delineate the molecular mechanisms fueling metabolic deregulation and tumorigenesis following LKB1 inactivation as well as translational promise of therapeutic strategies aimed at targeting LKB1-deficient tumors.

Keywords: AMP-activated protein kinase; Warburg; fluoro-deoxyglucose positron emission tomography; liver kinase B1; mammalian target of rapamycin complex 1; therapeutics.

Figure 1

Schematic representation of the Liver Kinase B1 dependent regulation of growth, metabolism and mitochondrial homeostasis through AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Both tumour suppressors (in blue) and oncogenes (in red) regulate mTORC1 and are frequently mutated in cancer. mTORC1 effectors S6K and 4E-binding protein 1 and mTORC1-regulated transcription factors such as sterol regulatory element-binding protein 1 (SREBP1) and HIF1α, cMYC and Cyclin D1 (in green) are involved in cell growth, lipid and glucose metabolism and angiogenesis. AMPK suppresses mTORC1 through activation of tuberous sclerosis complex 2 and raptor and regulates mitochondrial homeostasis through peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1 α) and Unc51 like kinase 1

Figure 2

Therapeutically targeting the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex (mTORC1) signaling pathways in liver kinase B1 (LKB1) -/- tumors. Schematic representation of therapeutic strategies targeting AMPK and the mTORC1 signaling pathway following LKB1 inactivation. (a) A representation of AMPK agonists that mimic cellular energy stress creating metabolic and oxidative stress that results in tumor cell death. (b) A representation of therapies targeting critical upstream and downstream effectors of mTORC1 in LKB1 -/- tumors