Abstract
The mTOR (mechanistic target of rapamycin) is the main regulator of important cellular processes, including cellular growth, proliferation, protein synthesis, protein remodeling, autophagy, and cell metabolism in response to nutrition status, growth factor, and stress signals. Previous studies demonstrated that mTOR signaling plays a crucial role in the function of adipose tissue such as adipogenesis, lipid metabolism, thermogenesis, and adipokine biosynthesis and release. Nutritional status in adipose tissues is different than its surrounding microenvironment, which receive altered metabolic ques. from the adipose tissues. In regard to its critical role in cellular processes, it is expected that obesity and related metabolic disorders will have direct role in dysregulation of mTOR signaling. Aberrant mTOR signaling is commonly observed in different types of cancer. Hyperactivation of mTORC1 pathway activates cell proliferation and decreased autophagy, which leads to initiation of tumor growth, progression, and angiogenesis. Another regulator of metabolic activity, adenosine monophosphate (AMP)-activated protein kinase (AMPK), maintains the energy homeostasis in response to metabolic alteration. Previous research demonstrated that AMPK is a key cellular energy sensor responsible for regulating the metabolic activity of brown and beige adipose tissues. AMPK has also been demonstrated to negatively regulate diabetes, cardiovascular disease, and other metabolic syndromes. Apart from metabolic syndrome and diabetes, the AMPK signaling has shown therapeutic potential due to its unique potential in regulating of cancer cell proliferation via cell metabolism reprogramming.. Previous reports suggest the tumor suppressive role of AMPK that sense the energy deficiency in solid tumors, thereby inhibit the cellular proliferation. However, recent data proposes that tumor cells gain growth advantage in oxygen and nutrient deprived condition via exploiting AMPK activation. In light of adipose tissue associated tumors, it is well known that adipose tissues activate inflammation in response oxygen deprivation. However, the role of altered metabolism, specifically interaction between adipose tissues and tumor microenvironment, in terms of mTOR and AMPK signaling is not well known.
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References
Abreu Velez AM, Howard MS (2015) Tumor-suppressor genes, cell cycle regulatory checkpoints, and the skin. N Am J Med Sci 7(5):176–188. https://doi.org/10.4103/1947-2714.157476
Adamovich Y, Adler J, Meltser V, Reuven N, Shaul Y (2014) AMPK couples p73 with p53 in cell fate decision. Cell Death Differ 21(9):1451–1459. https://doi.org/10.1038/cdd.2014.60
Ahmadian M, Abbott MJ, Tang T, Hudak CS, Kim Y, Bruss M, Hellerstein MK, Lee HY, Samuel VT, Shulman GI, Wang Y, Duncan RE, Kang C, Sul HS (2011) Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab 13(6):739–748. https://doi.org/10.1016/j.cmet.2011.05.002
Andò S, Gelsomino L, Panza S, Giordano C, Bonofiglio D, Barone I, Catalano S (2019) Obesity, leptin and breast cancer: epidemiological evidence and proposed mechanisms. Cancer 11(1):62. https://doi.org/10.3390/cancers11010062
Apontes P, Leontieva OV, Demidenko ZN, Li F, Blagosklonny MV (2011) Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture. Oncotarget 2(3):222–233. https://doi.org/10.18632/oncotarget.248
Arnold M, Pandeya N, Byrnes G, Renehan P, Stevens GA, Ezzati PM, Ferlay J, Miranda JJ, Romieu I, Dikshit R, Forman D, Soerjomataram I (2015) Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol 16(1):36–46. https://doi.org/10.1016/S1470-2045(14)71123-4
Baba Y, Nosho K, Shima K, Meyerhardt JA, Chan AT, Engelman JA, Cantley LC, Loda M, Giovannucci E, Fuchs CS, Ogino S (2010) Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer. Br J Cancer 103(7):1025–1033. https://doi.org/10.1038/sj.bjc.6605846
Balistreri CR, Caruso C, Candore G (2010) The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat Inflamm 2010:802078. https://doi.org/10.1155/2010/802078
Bao J, Zhu L, Zhu Q, Su J, Liu M, Huang W (2016) SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer. Oncol Lett 12(4):2409–2416. https://doi.org/10.3892/ol.2016.4988
Blüher M (2019) Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 15(5):288–298. https://doi.org/10.1038/s41574-019-0176-8
Cai H, Dong LQ, Liu F (2016) Recent advances in adipose mTOR signaling and function: therapeutic prospects. Trends Pharmacol Sci 37(4):303–317. https://doi.org/10.1016/j.tips.2015.11.011
Chakrabarti P, English T, Shi J, Smas CM, Kandror KV (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59(4):775–781. https://doi.org/10.2337/db09-1602
Chen J (2011) Multiple signal pathways in obesity-associated cancer. Obes Rev 12(12):1063–1070. https://doi.org/10.1111/j.1467-789X.2011.00917.x
Chen X, Xie C, Fan XX, Jiang ZB, Wong VK, Xu JH, Yao XJ, Liu L, Leung EL (2017) Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism. Oncotarget 8(56):96089–96102. https://doi.org/10.18632/oncotarget.21716
Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB (2016) Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne) 7:30. https://doi.org/10.3389/fendo.2016.00030
Clarke PR, Hardie DG (1990) Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J 9(8):2439–2446
Coelho M, Oliveira T, Fernandes R (2013) Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci 9(2):191–200. https://doi.org/10.5114/aoms.2013.33181
Conciatori F, Bazzichetto C, Falcone I, Pilotto S, Bria E, Cognetti F, Milella M, Ciuffreda L (2018) Role of mTOR signaling in tumor microenvironment: an overview. Int J Mol Sci 19(8):2453. https://doi.org/10.3390/ijms19082453
Corrêa LH, Corrêa R, Farinasso CM, de Sant’Ana Dourado LP, Magalhães KG (2017) Adipocytes and macrophages interplay in the orchestration of tumor microenvironment: new implications in cancer progression. Front Immunol 8:1129. https://doi.org/10.3389/fimmu.2017.01129
Cozzo AJ, Fuller AM, Makowski L (2017) Contribution of adipose tissue to development of cancer. Compr Physiol 8(1):237–282. https://doi.org/10.1002/cphy.c170008
Divella R, De Luca R, Abbate I, Naglieri E, Daniele A (2016) Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. J Cancer 7(15):2346–2359. https://doi.org/10.7150/jca.16884
Doerstling SS, O’Flanagan CH, Hursting SD (2017) Obesity and cancer metabolism: a perspective on interacting tumor-intrinsic and extrinsic factors. Front Oncol 7:216. https://doi.org/10.3389/fonc.2017.00216
Easton JB, Houghton PJ (2006) mTOR and cancer therapy. Oncogene 25(48):6436–6446. https://doi.org/10.1038/sj.onc.1209886
Engin AB, Engin A, Gonul II (2019) The effect of adipocyte-macrophage crosstalk in obesity-related breast cancer. J Mol Endocrinol 62(3):R201–R222. https://doi.org/10.1530/JME-18-0252
Faivre S, Djelloul S, Raymond E (2006a) New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol 33(4):407–420. https://doi.org/10.1053/j.seminoncol.2006.04.005
Faivre S, Kroemer G, Raymond E (2006b) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688. https://doi.org/10.1038/nrd2062
Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, DeBerardinis RJ, Siegel PM, Jones RG (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124. https://doi.org/10.1016/j.cmet.2012.12.001
Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102(23):8204–8209. https://doi.org/10.1073/pnas.0502857102
Friedrich MJ (2017) Global obesity epidemic worsening. JAMA 318(7):603. https://doi.org/10.1001/jama.2017.10693
Gadgeel SM, Lew DL, Synold TW, LoRusso P, Chung V, Christensen SD, Smith DC, Kingsbury L, Hoering A, Kurzrock R (2013) Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528. Cancer Chemother Pharmacol 72(5):1089–1096. https://doi.org/10.1007/s00280-013-2297-4
Ganapathy-Kanniappan S, Geschwind JF (2013) Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 12:152. https://doi.org/10.1186/1476-4598-12-152
Gonzalez-Angulo AM, Meric-Bernstam F, Chawla S, Falchook G, Hong D, Akcakanat A, Chen H, Naing A, Fu S, Wheler J, Moulder S, Helgason T, Li S, Elias I, Desai N, Kurzrock R (2013) Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. Clin Cancer Res 19(19):5474–5484. https://doi.org/10.1158/1078-0432.CCR-12-3110
Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM (2014) A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov 4(5):554–563. https://doi.org/10.1158/2159-8290.CD-13-0929
Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM (2009) mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15(2):148–159. https://doi.org/10.1016/j.ccr.2008.12.017
Hajri T, Han XX, Bonen A, Abumrad NA (2002) Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest 109(10):1381–1389. https://doi.org/10.1172/JCI14596
Han Y, Hu Z, Cui A, Liu Z, Ma F, Xue Y, Liu Y, Zhang F, Zhao Z, Yu Y, Gao J, Wei C, Li J, Fang J, Li J, Fan JG, Song BL, Li Y (2019) Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene. Nat Commun 10(1):623. https://doi.org/10.1038/s41467-019-08585-4
Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25(18):1895–1908. https://doi.org/10.1101/gad.17420111
Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12(19):5755–5763. https://doi.org/10.1158/1078-0432.CCR-06-0118
Holmes BF, Kurth-Kraczek EJ, Winder WW (1999) Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 87(5):1990–1995. https://doi.org/10.1152/jappl.1999.87.5.1990
Hopkins BD, Goncalves MD, Cantley LC (2016) Obesity and cancer mechanisms: cancer metabolism. J Clin Oncol 34(35):4277–4283. https://doi.org/10.1200/JCO.2016.67.9712
Huh JY, Park YJ, Ham M, Kim JB (2014) Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells 37(5):365–371. https://doi.org/10.14348/molcells.2014.0074
Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY, James DE (2013) Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 17(6):1009–1020. https://doi.org/10.1016/j.cmet.2013.04.010
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955–968. https://doi.org/10.1016/j.cell.2006.06.055
Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128. https://doi.org/10.1038/ncb1183
Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48(7):e245. https://doi.org/10.1038/emm.2016.81
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA, Vogelstein B Jr, Kinzler KW, Hruban RH, Papadopoulos N (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science (New York, N.Y.) 331(6021):1199–1203. https://doi.org/10.1126/science.1200609
Johnson AR, Milner JJ, Makowski L (2012) The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev 249(1):218–238. https://doi.org/10.1111/j.1600-065X.2012.01151.x
Kern L, Mittenbühler MJ, Vesting AJ, Ostermann AL, Wunderlich CM, Wunderlich FT (2018) Obesity-induced TNFα and IL-6 signaling: the missing link between obesity and inflammation-driven liver and colorectal cancers. Cancer 11(1):24. https://doi.org/10.3390/cancers11010024
Khandekar MJ, Cohen P, Spiegelman BM (2011) Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 11(12):886–895. https://doi.org/10.1038/nrc3174
Kim J, Guan KL (2019) mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol 21(1):63–71. https://doi.org/10.1038/s41556-018-0205-1
Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118(9):3051–3064. https://doi.org/10.1172/JCI34764
Kumar A, Lawrence JC, Jung DY Jr, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE (2010) Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59(6):1397–1406. https://doi.org/10.2337/db09-1061
Laplante M, Horvat S, Festuccia WT, Birsoy K, Prevorsek Z, Efeyan A, Sabatini DM (2012) DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity. Cell Metab 16(2):202–212. https://doi.org/10.1016/j.cmet.2012.07.008
Laplante M, Sabatini DM (2009a) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589–3594. https://doi.org/10.1242/jcs.051011
Laplante M, Sabatini DM (2009b) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19(22):R1046–R1052. https://doi.org/10.1016/j.cub.2009.09.058
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. https://doi.org/10.1016/j.cell.2012.03.017
Lee PL, Jung SM, Guertin DA (2017) The complex roles of mechanistic target of rapamycin in adipocytes and beyond. Trends Endocrinol Metab 28(5):319–339. https://doi.org/10.1016/j.tem.2017.01.004
Lengyel E, Makowski L, DiGiovanni J, Kolonin MG (2018) Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4(5):374–384. https://doi.org/10.1016/j.trecan.2018.03.004
Li W, Saud SM, Young MR, Chen G, Hua B (2015) Targeting AMPK for cancer prevention and treatment. Oncotarget 6(10):7365–7378. https://doi.org/10.18632/oncotarget.3629
Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44(5):479–496. https://doi.org/10.3109/10715761003667554
Liu R, Nikolajczyk BS (2019) Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond. Front Immonol 10:1587. https://doi.org/10.3389/fimmu.2019.01587
Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Beguinot F, Miele C (2019) Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci 20(9):2358. https://doi.org/10.3390/ijms20092358
Luo Z, Zang M, Guo W (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol 6(3):457–470. https://doi.org/10.2217/fon.09.174
Lyons CL, Roche HM (2018) Nutritional modulation of AMPK-impact upon metabolic-inflammation. Int J Mol Sci 19(10):3092. https://doi.org/10.3390/ijms19103092
Malley CO, Pidgeon GP (2016) The mTOR pathway in obesity driven gastrointestinal cancers: potential targets and clinical trials. BBA Clin 5:29–40. https://doi.org/10.1016/j.bbacli.2015.11.003
Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274. https://doi.org/10.1016/j.cell.2007.06.009
Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001
Mao Z, Zhang W (2018) Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 19(7):2043. https://doi.org/10.3390/ijms19072043
MarÃn-Aguilar F, Pavillard LE, Giampieri F, Bullón P, Cordero MD (2017) Adenosine monophosphate (AMP)-activated protein kinase: a new target for nutraceutical compounds. Int J Mol Sci 18(2):288. https://doi.org/10.3390/ijms18020288
Mayer IA, Arteaga CL (2016) The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med 67:11–28. https://doi.org/10.1146/annurev-med-062913-051343
Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36(6):320–328. https://doi.org/10.1016/j.tibs.2011.03.006
Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13(9):1016–1023. https://doi.org/10.1038/ncb2329
Munday MR, Campbell DG, Carling D, Hardie DG (1988) Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur J Biochem 175(2):331–338. https://doi.org/10.1111/j.1432-1033.1988.tb14201.x
Muoio DM, Seefeld K, Witters LA, Coleman RA (1999) AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem J 338(Pt 3):783–791
Murugan AK (2019) mTOR: role in cancer, metastasis and drug resistance. Semin Cancer Biol 59:92–111. https://doi.org/10.1016/j.semcancer.2019.07.003
Nakabayashi M, Werner L, Courtney KD, Buckle G, Oh WK, Bubley GJ, Hayes JH, Weckstein D, Elfiky A, Sims DM, Kantoff PW, Taplin ME (2012) Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU Int 110(11):1729–1735. https://doi.org/10.1111/j.1464-410X.2012.11456.x
Novikova DS, Garabadzhiu AV, Melino G, Barlev NA, Tribulovich VG (2015) AMP-activated protein kinase: structure, function, and role in pathological processes. Biochemistry (Mosc) 80(2):127–144. https://doi.org/10.1134/S0006297915020017
O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66(3):1500–1508. https://doi.org/10.1158/0008-5472.CAN-05-2925
Oda K, Uto H, Mawatari S, Ido A (2015) Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies. Clin J Gastroenterol 8(1):1–9. https://doi.org/10.1007/s12328-014-0548-5
Pajvani UB, Qiang L, Kangsamaksin T, Kitajewski J, Ginsberg HN, Accili D (2013) Inhibition of notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med 19(8):1054–1060. https://doi.org/10.1038/nm.3259
Paquette M, El-Houjeiri L, Pause A (2018) mTOR pathways in cancer and autophagy. Cancer 10(1):18. https://doi.org/10.3390/cancers10010018
Pi-Sunyer X (2009) The medical risks of obesity. Postgrad Med 121(6):21–33. https://doi.org/10.3810/pgm.2009.11.2074
Poltavets V, Kochetkova M, Pitson SM, Samuel MS (2018) The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front Oncol 8:431. https://doi.org/10.3389/fonc.2018.00431
Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8(3):224–236. https://doi.org/10.1016/j.cmet.2008.07.007
Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64. https://doi.org/10.3389/fonc.2014.00064
Pothiwala P, Jain SK, Yaturu S (2009) Metabolic syndrome and cancer. Metab Syndr Relat Disord 7(4):279–288. https://doi.org/10.1089/met.2008.0065
Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Bustos M, MartÃnez JA, Moreno-Aliaga MJ (2011) Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach. Biochim Biophys Acta 1807(6):664–678. https://doi.org/10.1016/j.bbabio.2010.11.004
Ramon Y, Cajal S, De Mattos-Arruda L, Sonenberg N, Cortes J, Peg V (2014) The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets. Clin Transl Oncol 16(11):937–941. https://doi.org/10.1007/s12094-014-1203-9
Rasmussen BB, Winder WW (1997) Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J Appl Physiol 83(4):1104–1109. https://doi.org/10.1152/jappl.1997.83.4.1104
Ricoult SJ, Manning BD (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 14(3):242–251. https://doi.org/10.1038/embor.2013.5
Ricoult SJ, Yecises JL, Ben-Sahra I, Manning BD (2016) Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 35(10):1250–1260. https://doi.org/10.1038/onc.2015.179
Riquelme I, Tapia O, Espinoza JA, Leal P, Buchegger K, Sandoval A, Bizama C, Araya JC, Peek RM, Roa JC (2016) The gene expression status of the PI3K/AKT/mTOR pathway in gastric cancer tissues and cell lines. Pathol Oncol Res 22(4):797–805. https://doi.org/10.1007/s12253-016-0066-5
Romieu I, Dossus L, Barquera S, Blottière HM, Franks PW, Gunter M, Hwalla N, Hursting SD, Leitzmann M, Margetts B, Nishida C, Potischman N, Seidell J, Stepien M, Wang Y, Westerterp K, Winichagoon P, Wiseman M, Willett WC (2017) Energy balance and obesity: what are the main drivers? Cancer Causes Control 28(3):247–258. https://doi.org/10.1007/s10552-017-0869-z
Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444(7121):847–853. https://doi.org/10.1038/nature05483
Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156:20–44. https://doi.org/10.1016/j.cell.2013.12.012
Sag D, Carling D, Stout RD, Suttles J (2008) Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181(12):8633–8641. https://doi.org/10.4049/jimmunol.181.12.8633
Salt IP, Hardie DG (2017) AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system. Circ Res 120(11):1825–1841. https://doi.org/10.1161/CIRCRESAHA.117.309633
Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290–303. https://doi.org/10.1016/j.cell.2010.02.024
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976. https://doi.org/10.1016/j.cell.2017.02.004
Scheller T, Hellerbrand C, Moser C et al (2015) mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma. Br J Cancer 112:841–850. https://doi.org/10.1038/bjc.2014.638
Shearer J, Fueger PT, Bracy DP, Wasserman DH, Rottman JN (2005) Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance. Diabetes 54(11):3133–3139. https://doi.org/10.2337/diabetes.54.11.3133
Shearer J, Fueger PT, Rottman JN, Bracy DP, Martin PH, Wasserman DH (2004) AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo. Am J Physiol Endocrinol Metab 287(5):E871–E877. https://doi.org/10.1152/ajpendo.00125.2004
Sjödahl G, Lauss M, Gudjonsson S, Liedberg F, Halldén C, Chebil G, Månsson W, Höglund M, Lindgren D (2011) A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS One 6(4):e18583. https://doi.org/10.1371/journal.pone.0018583
Srivastava RA, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS (2012) AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res 53(12):2490–2514. https://doi.org/10.1194/jlr.R025882
Steinberg GR, Carling D (2019) AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov 18(7):527–551. https://doi.org/10.1038/s41573-019-0019-2
Su B, Jacinto E (2011) Mammalian TOR signaling to the AGC kinases. Crit Rev Biochem Mol Biol 46(6):527–547. https://doi.org/10.3109/10409238.2011.618113
Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C et al (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57(23):5221–5225
Tumminia A, Vinciguerra F, Parisi M, Graziano M, Sciacca L, Baratta R, Frittitta L (2019) Adipose tissue, obesity and adiponectin: role in endocrine cancer risk. Int J Mol Sci 20(12):2863. https://doi.org/10.3390/ijms20122863
Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59(3):554–563. https://doi.org/10.2337/db09-0482
Wang Z, Feng X, Molinolo AA, Martin D, Vitale-Cross L, Nohata N, Ando M, Wahba A, Amornphimoltham P, Wu X, Gilardi M, Allevato M, Wu V, Steffen DJ, Tofilon P, Sonenberg N et al (2019) 4E-BP1 is a tumor suppressor protein reactivated by mTOR inhibition in head and neck cancer. Cancer Res 79(7):1438–1450. https://doi.org/10.1158/0008-5472.CAN-18-1220
Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21(3):297–308. https://doi.org/10.1016/j.ccr.2012.02.014
Watt MJ, Holmes AG, Pinnamaneni SK, Garnham AP, Steinberg GR, Kemp BE, Febbraio MA (2006) Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 290(3):E500–E508. https://doi.org/10.1152/ajpendo.00361.2005
WÅ‚odarczyk M, Nowicka G (2019) Obesity, DNA damage, and development of obesity-related diseases. Int J Mol Sci 20(5):1146. https://doi.org/10.3390/ijms20051146
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484. https://doi.org/10.1016/j.cell.2006.01.016
Yang Y, Dong R, Hu D, Chen Z, Fu M, Wang DW, Xu X, Tu L (2017) Liver kinase B1/AMP-activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice. Cell Physiol Biochem 42(2):761–779. https://doi.org/10.1159/000478068
Ye Y, Liu H, Zhang F, Hu F (2019) mTOR signaling in Brown and Beige adipocytes: implications for thermogenesis and obesity. Nutr Metab (Lond) 16:74. https://doi.org/10.1186/s12986-019-0404-1
Yen CJ, Izzo JG, Lee DF, Guha S, Wei Y, Wu TT, Chen CT, Kuo HP, Hsu JM, Sun HL, Chou CK, Buttar NS, Wang KK, Huang P, Ajani J, Hung MC (2008) Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett’s-associated esophageal adenocarcinoma. Cancer Res 68(8):2632–2640. https://doi.org/10.1158/0008-5472.CAN-07-5460
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174. https://doi.org/10.1172/JCI13505
Zou Z, Tao T, Li H, Zhu X (2020) mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci 10:31. https://doi.org/10.1186/s13578-020-00396-1
Acknowledgement
IB acknowledge supports from Department of Cardio Vascular Biology, Oklahoma Medical Research Foundation, Oklahoma, USA. SKM acknowledge support from Ramjas College, University of Delhi. SS acknowledges support from Central University of Punjab, Bathinda, support from ICMR (33/6/2019-TF/Rare/BMS) and DST-FIST (SR/FST/LS-I/2017/49-C).
Conflict of Interest
IB, SKM and SS declare no conflict of interest.
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Biswas, I., Maurya, S.K., Senapati, S. (2021). mTOR and AMP-Activated Protein Kinase in Obesity and Cancer. In: Kumar, S., Gupta, S. (eds) Obesity and Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-16-1846-8_5
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