Browse > Article
http://dx.doi.org/10.7314/APJCP.2013.14.7.4033

LKB1/AMPK/mTOR Signaling Pathway in Non-small-cell Lung Cancer  

Han, Dong (Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University)
Li, Shao-Jun (Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University)
Zhu, Yan-Ting (Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University)
Liu, Lu (Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University)
Li, Man-Xiang (Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.7, 2013 , pp. 4033-4039 More about this Journal
Abstract
Links between cancer and metabolism have been suggested for a long time but compelling evidence for this hypothesis came from the recent molecular characterization of the LKB1/AMPK signaling pathway as a tumor suppressor axis. Besides the discovery of somatic mutations in the LKB1 gene in certain type of cancers, a critical emerging point was that the LKB1/AMPK axis remains generally functional and could be stimulated by pharmacological molecules such as metformin in cancer cells. In addition, AMPK plays a central role in the control of cell growth, proliferation and autophagy through the regulation of mTOR activity, which is consistently deregulated in cancer cells. Targeting of AMPK/mTOR is thus an attractive strategy in the development of therapeutic agents against non-small-cell lung cancer (NSCLC). In this review, the LKB1/AMPK/mTOR signaling pathway is described, highlighting its protective role, and opportunities for therapeutic intervention, and clinical trials in NSCLC.
Keywords
LKB1; AMPK; mTOR; NSCLC; therapeutic target;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Chapuis N, Tamburini J, Green AS, et al (2010). Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. Leukemia, 24, 1686-99.   DOI   ScienceOn
2 Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J (2008). Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A, 105, 17414-9.   DOI   ScienceOn
3 Don AS, Hogg PJ (2004). Mitochondria as cancer drug targets. Trends Mol Med, 10, 372-8.   DOI   ScienceOn
4 Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330, 1304-5.   DOI   ScienceOn
5 Feldman ME, Apsel B, Uotila A, et al (2009). Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol, 7, e38.   DOI   ScienceOn
6 Guertin DA, Sabatini DM (2007). Defining the role of mTOR in cancer. Cancer Cell, 12, 9-22.   DOI   ScienceOn
7 Guertin DA, Stevens DM, Saitoh M, et al (2009). mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell, 15, 148-59.   DOI   ScienceOn
8 Gwinn DM, Shackelford DB, Egan DF, et al (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell, 30, 214-26.   DOI   ScienceOn
9 Hahn-Windgassen A, Nogueira V, Chen CC, et al (2005). Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem, 280, 32081-9.   DOI   ScienceOn
10 Han S, Khuri FR, Roman J (2006). Fibronectin stimulates nonsmall cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res, 66, 315-23.   DOI   ScienceOn
11 Han S, Roman J (2006). Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther, 5, 430-7.   DOI   ScienceOn
12 Hardie DG (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol, 8, 774-85.   DOI   ScienceOn
13 Hardie DG (2011). AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev, 25, 1895-908.   DOI   ScienceOn
14 Hawley SA, Boudeau J, Reid JL, et al (2003). Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol, 2, 28.   DOI   ScienceOn
15 Hemminki A, Markie D, Tomlinson I, et al (1998). A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature, 391, 184-7.   DOI   ScienceOn
16 Holz MK, Ballif BA, Gygi SP, Blenis J (2005). mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell, 123, 569-80.   DOI   ScienceOn
17 Horman S, Vertommen D, Heath R, et al (2006). Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem, 281, 5335-40.
18 Huang J, Manning BD (2008). The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J, 412, 179-90.   DOI   ScienceOn
19 Huang X, Wullschleger S, Shpiro N, et al (2008). Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J, 412, 211-21.   DOI   ScienceOn
20 Hwang SK, Piao L, Lim HT, et al (2010). Suppression of lung tumorigenesis by leucine zipper/EF hand-containing transmembrane-1. PLoS One, 5.
21 Inoki K, Zhu T, Guan KL (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell, 115, 577-90.   DOI   ScienceOn
22 Jenne DE, Reimann H, Nezu J, et al (1998). Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet, 18, 38-43.   DOI   ScienceOn
23 Jacinto E, Loewith R, Schmidt A, et al (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol, 6, 1122-8.   DOI   ScienceOn
24 Jemal A, Bray F, Center M, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.   DOI
25 Jemal A, Siegel R, Xu J, Ward E (2010). Cancer statistics, 2010. CA Cancer J Clin, 60, 277-300.   DOI
26 Ji H, Ramsey MR, Hayes DN, et al (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature, 448, 807-10.   DOI   ScienceOn
27 Jin HO, Hong SE, Woo SH, et al (2012). Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition. Cell Death Dis, 3, e319.   DOI   ScienceOn
28 Jin Q, Feng L, Behrens C, et al (2007). Implication of AMPactivated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin. Cancer Res, 67, 11630-9.   DOI   ScienceOn
29 Jones RG, Plas DR, Kubek S, et al (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell, 18, 283-93.   DOI   ScienceOn
30 Khan N, Afaq F, Khusro FH, et al (2012). Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer, 130, 1695-705.   DOI   ScienceOn
31 Lee SO, Abdelrahim M, Yoon K, et al (2010). Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res, 70, 6824-36.   DOI   ScienceOn
32 Matsumoto S, Iwakawa R, Takahashi K, et al (2007). Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene, 26, 5911-8.   DOI   ScienceOn
33 Lee SO, Andey T, Jin UH, et al (2012). The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene, 31, 3265-76.   DOI   ScienceOn
34 Liu L, Cash TP, Jones RG, et al (2006). Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell, 21, 521-31.   DOI   ScienceOn
35 Mankouri J, Tedbury PR, Gretton S, et al (2010). Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A, 107, 11549-54.   DOI   ScienceOn
36 Memmott RM, Gills JJ, Hollingshead M, et al (2008). Phosphatidylinositol ether lipid analogues induce AMPactivated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells. Cancer Res, 68, 580-8.   DOI   ScienceOn
37 Nanjundan M, Byers LA, Carey MS, et al (2010). Proteomic profiling identifies pathways dysregulated in non-small cell lung cancer and an inverse association of AMPK and adhesion pathways with recurrence. J Thorac Oncol, 5, 1894-904.   DOI   ScienceOn
38 Rauch A, Schellmoser S, Kraus C, et al (2001). First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet, 99, 338-42.   DOI   ScienceOn
39 Rothbart SB, Racanelli AC, Moran RG (2010). Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res, 70, 10299-309.   DOI   ScienceOn
40 Sanchez-Cespedes M, Parrella P, Esteller M, et al (2002). Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res, 62, 3659-62.
41 Shackelford DB, Vasquez DS, Corbeil J, et al (2009). mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci U S A, 106, 11137-42.   DOI   ScienceOn
42 Sanli T, Liu C, Rashid A, et al (2011). Lovastatin sensitizes lung cancer cells to ionizing radiation: modulation of molecular pathways of radioresistance and tumor suppression. J Thorac Oncol, 6, 439-50.   DOI
43 Sanli T, Rashid A, Liu C, et al (2010). Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys, 78, 221-9.   DOI   ScienceOn
44 Shackelford DB, Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer, 9, 563-75.   DOI   ScienceOn
45 Shao JJ, Zhang AP, Qin W, et al (2012). AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells. Biochem Biophys Res Commun, 423, 448-53.   DOI   ScienceOn
46 Shaw RJ, Bardeesy N, Manning BD, et al (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell, 6, 91-9.   DOI   ScienceOn
47 Shaw RJ, Cantley LC (2006). Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 441, 424-30.   DOI   ScienceOn
48 Storozhuk Y, Sanli T, Hopmans SN, et al (2012). Chronic modulation of AMP-Kinase, Akt and mTOR pathways by ionizing radiation in human lung cancer xenografts. Radiat Oncol, 7, 71.   DOI
49 Street A, Macdonald A, Crowder K, Harris M (2004). The Hepatitis C virus NS5A protein activates a phosphoinositide 3-kinase-dependent survival signaling cascade. J Biol Chem, 279, 12232-41.   DOI   ScienceOn
50 Tamm I, Wang Y, Sausville E, et al (1998). IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res, 58, 5315-20.
51 Vaira V, Lee CW, Goel HL, et al (2007). Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene, 26, 2678-84.   DOI   ScienceOn
52 Wang HW, Lin CP, Chiu JH, et al (2007). Reversal of inflammation-associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin. Int J Cancer, 120, 2019-27.   DOI   ScienceOn
53 Wang X, Ling MT, Guan XY, et al (2004). Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene, 23, 474-82.   DOI   ScienceOn
54 William WN, Kim JS, Liu DD, et al (2012). The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival. Ann Oncol, 23, 78-85.   DOI
55 Woods A, Johnstone SR, Dickerson K, et al (2003). LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol, 13, 2004-8.   DOI   ScienceOn
56 Wullschleger S, Loewith R, Hall MN (2006). TOR signaling in growth and metabolism. Cell, 124, 471-84.   DOI   ScienceOn
57 Zhang XK (2007). Targeting Nur77 translocation. Expert Opin Ther Targets, 11, 69-79.   DOI
58 Zheng B, Jeong JH, Asara JM, et al (2009). Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell, 33, 237-47.   DOI   ScienceOn