Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Abstract

The precise role of 5'AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. Although it is well established that activation of this energy sensor inhibits the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a "conditional" tumor suppressor and "contextual" oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation, and provides an overview of the most relevant data available on AMPK activation and AMPK-activating drugs in human studies.

Figure 1. Mechanisms of AMPK activation

AMPK functions as a metabolic sensor that is activated by metabolic stress induced by hypoxia, nutrient deprivation, and drugs/compounds [e.g. biguanides, 2-deoxyglucose (2-DG)], AMP mimetic, direct AMPK activators, or reactive oxygen species (ROS). For the full activity of the kinase, a phosphorylation at the residue Thr172 in the catalytic loop is required. The main upstream kinases are the Liver kinase B1 (LKB1), the Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and the transforming growth factor beta-activated kinase 1 (TAK1). Uncharacterized protein phosphates (PPs) can reverse this phosphorylation.

Figure 2. AMPK-mediated metabolic and signaling reprogramming

Once activated, AMPK switches off anabolic pathways while turning on catabolic pathways to restore energy homeostasis. Thus, AMPK controls pathways involved in metabolism, cell growth, and survival. Red lines indicate direct activation, whereas inhibition is depicted in blue. A question mark indicates that it is not yet certain that the protein is directly phosphorylated. Abbreviations: ACC1/ACC2, acetyl-CoA carboxylases 1/2; HMGR, HMG-CoA reductase; SREBP, sterol response element binding protein; CHREBP, carbohydrate response element binding protein; FAO, fatty acid oxidation; TIF-1A, transcription initiation factor-1A; mTORC1, mammalian target of rapamycin complex 1; TSC2, tuberous sclerosis complex 2, GLUT1/4, glucose transporter 1, 4; PFKFB2/3,6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases 2 and 3; TBC1D1, TBC1 domain protein-1; SIRT1, sirtuin 1; PGC-1α, PPARγ-coactivator-1α; ULK1, Unc51-like kinase-1, AMOTL1, angiomotin like 1; YAP, Yes-associated protein 1.

Figure 3. Main mechanisms through which AMPK can exert its double-faced role in cancer

AMPK activation triggers cellular processes that can both suppress and promote tumor development/progression by activating different downstream pathways in a context specific manner. Abbreviations: mTORC1, mammalian target of rapamycin complex 1; HIF-1α, hypoxia-inducible factor 1-alpha; YAP, Yes-associated protein 1; Foxo3a, forkhead box O3; AR, androgen receptor; FAO, fatty acid oxidation; ACC2, acetyl-CoA carboxylases 2; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; ULK1, Unc51-like kinase-1.

Figure 4. AMPK functions as “conditional” tumor suppressor and “contextual” tumor promoter

The outcome of AMPK activation in cancer is affected by the genetic context, metabolic dependency of cancer cells, and the surrounding microenvironment. Differences in the intensity/duration of AMPK activation (e.g. physiological activation vs. drug-induced supra-physiological activation) as well as in the expression/activation of specific subunits of the heterotrimer contribute to the anti- vs pro-tumorigenic role of AMPK in different cancer types.

Figure 5. Mechanisms by which biguanides are therapeutically beneficial in LKB1-positive and negative tumors

A. Metformin or phenformin activates AMPK in pre-neoplastic cells with functional LKB1/AMPK pathway, restraining their growth and proliferation and thus delaying the onset of tumorigenesis; B. Cancer cells, in which the LKB1-AMPK pathway is not functional, cannot restore biguanides-induced energy stress and they are more sensitive to cell death (biguanide paradox).