Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 Cancer Review Research AMPK: A Contextual Oncogene or Tumor Suppressor? Jiyong Liang and Gordon B. Mills Abstract The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the LKB1/STK11 tumor suppressor (LKB1 mutations cause the Peutz-Jegher cancer predisposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. However, AMPK has recently been shown to promote cancer cell survival in the face of extrinsic and intrinsic stressors including bioenergetic, growth factor, and oncogene stress compatible with studies showing that AMPK is required for oncogenic transformation. Thus, whether AMPK acts as a bona fide tumor suppressor or a contextual oncogene and, of particular importance, whether AMPK should be targeted for activation or inhibition during cancer therapy, is controversial and requires clarification. We aim to initiate discussions of these critical questions by reviewing the role of AMPK with an emphasis on cancer cell adaptation to microenvironment stress and therapeutic intervention. Cancer Res; 73(10); 1–7. Ó2013 AACR. AMPK Regulation increasing number of drugs and xenobiotics, such as paclitaxel, The AMPK holoenzymes metformin, and resveratrol. However, it is important to make a Kinase-competent AMP-activated protein kinase (AMPK) clear distinction between the effects of energy stress and AMPK complexes exist in mammalian cells as heterotrimers com- activation per se before any cellular outcome can be appro- posed of one a catalytic and 2 b and g regulatory subunits priately attributed to AMPK (3). As an example, metformin, encoded by the PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, which has been proposed to be an AMPK "agonist," has no PRKAG2, and PRKAG3 genes. To add to the complexity, mul- direct effect on either AMPK or its upstream kinase LKB1 (4). tiple potentially functional splice variants have been identified. Instead, metformin inhibits the mitochondrial electron trans- As a result, multiple AMPK isoenzyme complexes are likely port chain complex I disrupting energy homeostasis (5) and present in any cell depending on the tissue and cell specificity also alters mTOR function independently of AMPK and TSC2 of individual subunit expression. (6). Allosteric versus "agonistic" activation T-loop phosphorylation AMPK is unique as a kinase in terms of functioning as a AMPK activation requires phosphorylation at the conserved sensor of cellular energy levels. Mammalian AMPKg has 3 CBS threonine residue (Thr172 in case of human and murine adenosine phosphate binding sites; ATP, ADP, and AMP AMPKa2) within the activation loop (i.e., the T-loop) of the compete for CBS1 and CBS3, whereas CBS4 is constitutively catalytic subunit. LKB1 is the primary kinase phosphorylating occupied by AMP independent of adenyl nucleotide concen- this site; however, depending on cellular and activation con- trations. AMP/ADP binding promotes T-loop phosphorylation text, other kinases, including CaMKKb and TAK1, can activate and allosteric activation of a subunits, whereas ATP binding AMPK. AMPK activation can also be affected by Thr172 inhibits the kinase complex (1). Thus, AMPK activation is dephosphorylation, although the responsible phosphatase(s) fi regulated by adenylate energy charge rather than solely by awaits identi cation (1, 2). The relative contribution of Thr172 relative levels of AMP and ATP as thought previously. Other phosphorylation/dephosphorylation and allosteric activation metabolic intermediates including glycogen and NADH can of AMPK by nucleotide binding remains controversial. bind AMPK complexes, but whether they alter AMPK activity remains undefined (2). In theory, any stimulus that alters AMPK and Cancer cellular energy levels alters AMPK activation, including an AMPK and "stress management" in cancer cells AMPK functions physiologically to allow cells to cope with stress, including metabolic, growth factor deprivation, and Authors' Affiliation: Systems Biology, The University of Texas MD Ander- son Cancer Center, Houston, Texas oncogenic stress (Fig. 1). AMPK activates catabolic and inhibits anabolic metabolism, a scenario that is not compatible with Corresponding Authors: Jiyong Liang, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. cell proliferation and is consistent with a tumor suppressor Phone: 713-834-6161; Fax: 713-563-4235; E-mail:[email protected]; role. However, although AMPK, when highly activated, can and Gordon B. Mills, E-mail: [email protected] potently inhibit cell proliferation and tumor growth, loss of doi: 10.1158/0008-5472.CAN-12-3876 AMPK is not sufficient to confer cell proliferation in the Ó2013 American Association for Cancer Research. absence of adequate nutrients and growth factors, which is www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 Liang and Mills AMPK TBC1D1 PFKFB3 PGC1A GLUT1 ACC1 TSC2 Figure 1. AMPK promotes cell ACC2 ULK1 survival. Under conditions where growth factors, nutrients, Glycolysis oxygen, adhesion, and pH IRS1 Glutamine Glucose p27 are unfavorable for cell metabolism uptake proliferation, as well as under oncogenic stress induced by deregulated Ras and Myc NADPH mTOR oncogenes, AMPK can activate multiple pathways that maintain bioenergetic homeostasis to support cell survival. Which β- HIF1 downstream processes oxidation Autophagy manifest under basal conditions and in response to particular stress conditions as well as the functional outcomes Energy Cyclin are dependent on the cellular AKT TBC1D4 Nutrients homeostasis Cdks context and the duration and magnitude of the stress. GSK3β Survival under stress © 2013 American Association for Cancer Research distinct from defects in genome surveillance genes that lead to inherited condition characterized primarily by benign intesti- cell division despite unrepaired DNA errors. Instead, loss of nal hamartomatous polyps and mucocutaneous pigmentation bioenergetic homeostasis leads to programmed cell death in associated with increased risk of developing malignant cells lacking either LKB1 or AMPK but not normal cells tumors of multiple lineages (13–16). Somatic LKB1 mutations identically stressed (7–10). Further, cells lacking AMPK are are found in lung and cervical cancer; epigenetic inactivation of resistant to oncogenic transformation (11). We posit that LKB1, although rare, has been reported in sporadic papillary þ À AMPK may act as a conditional tumor suppressor or oncogene breast cancer. LKB1 haploinsufficiency (LKB1 / ) in mice depending on the degree of AMPK activation, the particular gives rise to phenotypes similar to human PJS with the for- AMPK isoforms present, and other processes activated in the mation of polyps in the gastrointestinal tract and increased cell (12). It is possible that modest activation of AMPK engages frequency of liver, bone, and endometrial cancer (13). Thus, cell protective mechanisms resulting in oncogene-like activi- LKB1 is a validated tumor suppressor gene. ties, whereas increased magnitude or duration of stress could In contrast with LKB1, AMPK a, b, and g subunits are rarely induce growth arrest or cell death exhibiting a tumor sup- (<3% for any subunit) somatically mutated in human cancers pressor function. and indeed are amplified more frequently than mutated (cancergenome.nih.gov/), and there is no evidence for a germ- AMPK-related kinases other than AMPK may mediate line cancer predisposition syndrome involving AMPK subunits. some of the tumor suppressor functions of LKB1 Complete loss of AMPK function is embryonically lethal in Germline mutations in LKB1 are the cause of Peutz-Jegher mice. Conditional AMPK knockout models have been created cancer predisposition syndrome (PJS), a rare and dominantly (17); however, the role of AMPK in tumorigenesis has not been OF2 Cancer Res; 73(10) May 15, 2013 Cancer Research Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 AMPK Regulates Cancer Metabolism extensively studied in these models. Similar to LKB1 deletion and mTORC1 (37). Thus, AMPK-related kinases rather than (14, 18), murine fibroblasts lacking both catalytic isoforms of AMPK may mediate the tumor suppressor role of LKB1 (38, 39), AMPK are resistant to oncogenic transformation (11), which is although NuAK1 (also known as ARK5), NuAK2, SIK1, SIK2, consistent with AMPK and an intact energy-sensing mecha- and SIK3 have been linked to tumor formation, invasion, and nism being required during oncogenesis. Although loss of metastasis (40–44). AMPK on its own is insufficient to provoke tumor formation in mice, inactivation of AMPKa1, the sole catalytic subunit in AMPK and the p53 tumor suppressor murine B-cell lineages, can accelerate Myc-driven lymphoma- AMPK regulates p53 acetylation and phosphorylation (45, genesis (19). In contrast, deletion of the a2 but not the a1 46), again leading to the perception that AMPK functions as a subunit of AMPK increases susceptibility to H-RasV12– tumor suppressor. However, AMPK-dependent p53 activation induced transformation in murine fibroblasts (20), raising an promotes