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The Long and Winding Road to Rational Treatment of Cancer Associated with LKB1/AMPK/TSC/Mtorc1 Signaling

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The Long and Winding Road to Rational Treatment of Cancer Associated with LKB1/AMPK/TSC/Mtorc1 Signaling Oncogene (2011) 30, 2289–2303 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling W van Veelen, SE Korsse1, L van de Laar1 and MP Peppelenbosch Department of Gastroenterology and Hepatology, Erasmus Medical University Center, Rotterdam, The Netherlands The liver kinase B1 (LKB1)/adenosine mono-phosphate- The metabolic LKB1/AMPK/TSC/mTORC1 signaling activated protein kinase (AMPK)/tuberous sclerosis pathway complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical The liver kinase B1 (LKB1)/adenosine mono phosphate signaling pathway that integrates information on the activated protein kinase (AMPK)/tuberous sclerosis metabolic and nutrient status and translates this into complex (TSC)/mammalian target of rapamycin regulation of cell growth. Alterations in this pathway are (mTOR) complex 1 (mTORC1) signaling pathway associated with a wide variety of cancers and hereditary signaling pathway is central in regulating cellular hamartoma syndromes, diseases in which hyperactivation metabolism and cell growth by integrating information of mTORC1 has been described. Specific mTORC1 regarding the intracellular energy and oxygen status, the inhibitors have been developed for clinical use, and these presence of growth factors and nutrient availability. drugs have been anticipated to provide efficient treatment Under circumstances of sufficient energy and nutrient for these diseases. In the present review, we provide an sources, this metabolic pathway stimulates cell growth. overview of the metabolic LKB1/AMPK/TSC/mTORC1 In cases of stress, metabolic processes are adjusted to pathway, describe how its aberrant signaling associates restore resources in the cell. with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when LKB1/AMPK signaling targeting this signaling pathway. A careful examination of LKB1 (also referred to as serine/threonine kinase 11) preclinical and clinical studies performed with rapamycin is a 50 kDa serine/threonine kinase and is ubiquitously or derivatives thereof shows that although results are expressed in adult and fetal tissues, particularly in encouraging, we are only half way in the long and winding pancreas, liver, testes and skeletal muscle (Hemminki road to design rationale treatment targeted at the LKB1/ et al., 1998; Jenne et al., 1998). Lacking a nuclear export AMPK/TSC/mTORC1 pathway. Inherited cancer syn- domain of its own, in the absence of stimulation, LKB1 dromes associated with this pathway such as the Peutz– is retained in the nucleus in an inactive state (Figure 1). Jeghers syndrome and TSC, provide perfect models to Activation of LKB1 is associated with its translocation study the relationship between genetics and disease to the cytoplasm, which is induced upon formation of a phenotype, and to delineate the complexities that underlie heterotrimer with the STE20-related adaptor protein a translation of biochemical and genetical information to (STRADa) and scaffolding mouse 25 protein (MO25) clinical management, and thus provide important clues for (Baas et al., 2003; Boudeau et al., 2003; Brajenovic et al., devising novel rational medicine for cancerous diseases in 2004) (Figure 1). By facilitating the binding of exportins general. to LKB1 and acting as a competitor for importin-a/b, Oncogene (2011) 30, 2289–2303; doi:10.1038/onc.2010.630; STRADa prevents nuclear re-localization of LKB1 published online 24 January 2011 (Dorfman and Macara, 2008) (Figure 1). MO25 merely serves as a stabilizer of the LKB1-STRADa interaction Keywords: mTOR; rapamycin; hamartoma syndromes; (Boudeau et al., 2003). In addition to inducing its cancer; PTEN/PI3K/PKB signaling translocation, LKB1-STRADa interaction also results in LKB1 (auto) phosphorylation at various residues. However, the functional relevance of this remains debatable, as prevention of phosphorylation does not appear to affect LKB1 kinase activity (Jansen et al., 2009). When activated, LKB1 phosphorylates and activates Correspondence: Professor MP Peppelenbosch, Department of AMPKa and its related serine/threonine kinases Gastroenterology and Hepatology, Erasmus MC, Room L-457, (Figure 1) (Hawley et al., 2003; Lizcano et al., 2004; ‘s Gravendijkwal 230, Rotterdam 3015 CE, The Netherlands. Shaw et al., 2004; Jaleel et al., 2005; Lim et al., 2010). E-mail: [email protected] 1These authors contributed equally to this work. Via the regulation of MARK isoforms and PAR Received 13 October 2010; revised and accepted 15 December 2010; proteins, LKB1 establishes cell polarity (Figure 1) published online 24 January 2011 (Spicer et al., 2003; Lizcano et al., 2004). AMPKa is Road to treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling W van Veelen et al 2290 plasma memb rane low glucose low oxygen AMPKα1, AMPKα2 plasma NUAK1, NUAK2 membrane SIK1, SIK2 QSK ↑ AMP p MARK1, MARK2, MARK3, MARK4 STRADα translocation BRSK1, BRSK2 MO25 SNRK LKB1 active GLUT4 p AMPKγAMPKβ LKB1 ↑ 2+ Ca CaMKK p AMPKα STRADα MO25 LKB1 PP2A, PP2C STRADα MO25 β cytoplasm a nd Imp α export TSC2 FOXO3 ↑ NAD+ ACC1 Imp α dependent import raptor HNF4 ACC2 Exp7 or CRM1 dependent export P53 PGC1α HMGCR passive diffusion Exp7 or CRM1 nucleus dependent P27 HDAC LKB1 LKB1 CRTC2 SIRT1 STRADα STRADα inactive MO25 MO25 Figure 1 Activation and translocation of LKB1. LKB1 is activated by its translocation from the nucleus to the cytoplasm. Normally, LKB1 remains in the nucleus in an inactive state. Upon activation, LKB1 is bound by STE20-related adaptor protein a (STRADa) and mouse protein 25 (MO25), proteins that enter the CELL GROWTH and METABOLISM nucleus either by passive diffusion or active import by importins a/b (Impa, Impb). The stable LKB1/STRADa/MO25 complex is Figure 2 LKB1/AMPK signaling. The LKB1/AMPK signaling actively exported out of the nucleus by exportin 7 and CRM1. In pathway regulates cell growth and metabolism via various down- the cytoplasm, LKB1 exerts its serine/threonine kinase activity by stream effectors. Metabolic stress induced by, for example, low phosphorylating and activating the 14 members of the AMPK glucose or oxygen levels increases intracellular AMP/ATP ratios. serine/threonine kinase family regulating cell polarity, energy AMP is bound by the AMP-dependent protein kinase g subunit metabolism and cell growth. (AMPKg), which forms a complex with AMPKa and -b. Upon formation of this complex, AMPKa is phosphorylated by LKB1. AMPKa can also be phosphorylated by calcium/calmodulin- dependent protein kinase kinase (CaMKK) and is dephosphory- activated by LKB1 in response to energy stress. When, lated by the protein phosphatases PP2A and PP2C. The activated due to either excessive ATP consumption or in the case AMPK complex induces translocation of the glucose importer of hypoxia, reduced aerobic ATP production, cellular GLUT4 to the plasma membrane to enhance glucose uptake and regulates downstream signaling controlling gene transcription and AMP/ATP ratios are increased (Figure 2). This is sensed metabolic processes. Together, this results in the restoration of the by AMPK, which through binding of AMP undergoes a energy balance in the cell. conformational change, upon which it can be phos- phorylated by LKB1 (Figure 2) (Alessi et al., 2006; Hardie, 2007; Jansen et al., 2009). AMPKa can also be downstream effectors of AMPK is TSC2 as described in phosphorylated by calcium/calmodulin-dependent pro- more detail below. In conclusion, LKB1/AMPK signal- tein kinase kinase, which is triggered through influx of ing serves to coordinate energy metabolism, cell polarity calcium (Figure 2) (Hawley et al., 1995). The phosphor- and cell growth, processes which are all crucial in the ylation of AMPKa is reversed by the phosphatases development of cancer. PP2A and PP2C (Figure 2) (Moore et al., 1991). LKB1/AMPK signaling induces several cellular pro- cesses, one of which is the control of energy metabolism Regulation of the TSC1:TSC2 complex through regulation of several downstream targets, The TSC1:TSC2 complex exists as a heterodimer of including the metabolic enzymes acetyl-CoA carbox- two proteins, the 130 kDa TSC1 (also referred to as ylase and HMG-CoA reductase (Figure 2) (Carling hamartin) and the 200 kDa TSC2 (also referred to as et al., 1987). By suppressing energy-consuming processes tuberin) (Huang and Manning, 2008). TSC1 and TSC2 such as glycogen and lipid synthesis on the one hand, are widely expressed in human tissues, such as heart, and enhancing energy-gaining pathways such as glyco- brain, lung, liver, kidney, pancreas and skeletal muscle lysis on the other, AMPK activation aids in restoration (Consortium, 1993; van Slegtenhorst et al., 1997; Huang of the cellular energy status (Kola et al., 2006). In line, and Manning, 2008). The two proteins interact through AMPK activation induces relocalization of the glucose coiled-coil domains to form a stable, functional hetero- importer GLUT4 to the plasma membrane (Figure 2) dimer (van Slegtenhorst et al., 1998). The C-terminal (Kurth-Kraczek et al., 1999). In addition, LKB1/AMPK region of TSC2 shows homology to the Rap GTPase signaling regulates factors involved in cell cycle regula- activating protein, and GTPase activating protein tion, survival and gene transcription (Figure 2) (Jansen activity to various G-proteins
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