MTOR in viral hepatitis and hepatocellular carcinoma: Function and treatment

BioMed Research International

Volumn 2014, Issue , 2014, Pages

  Wang, Zhuo ^a   Jin, Wei ^a   Jin, Hongchuan ^a   Wang, Xian ^a  

^a ZHEJIANG UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC AGENT; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; TARGET OF RAPAMYCIN KINASE;

ANTINEOPLASTIC ACTIVITY; CANCER CHEMOTHERAPY; CANCER INHIBITION; DRUG POTENCY; DRUG TOLERABILITY; HEPATITIS B; HEPATITIS C; HUMAN; LIVER CELL CARCINOMA; MOLECULARLY TARGETED THERAPY; OUTCOME ASSESSMENT; PROTEIN STRUCTURE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY MECHANISM; REVIEW; VIRUS HEPATITIS; ANIMAL; ANTAGONISTS AND INHIBITORS; CARCINOMA, HEPATOCELLULAR; FEMALE; GENETICS; HEPATITIS; LIVER NEOPLASMS; MALE; PATHOLOGY; VIROLOGY;

ANIMALS; CARCINOMA, HEPATOCELLULAR; FEMALE; HEPATITIS; HUMANS; LIVER NEOPLASMS; MALE; PROTEIN KINASE INHIBITORS; TOR SERINE-THREONINE KINASES;

EID: 84899527393     PISSN: 23146133     EISSN: 23146141     Source Type: Journal    
DOI: 10.1155/2014/735672     Document Type: Review

References (90)

1. Bosch F. X.; Ribes J.; Díaz M.; Cléries R.; Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004 127 S5 S16 2-s2.0-7044229778 10.1053/j.gastro.2004.09.011 (Pubitemid 39423365)
2. Cotler S. J.; Hay N.; Xie H.; Chen M. L.; Xu P. Z.; Layden T. J.; Guzman G.; Immunohistochemical expression of components of the Akt-mTORC1 pathway is associated with hepatocellular carcinoma in patients with chronic liver disease. Digestive Diseases and Sciences 2008 53 3 844 849 2-s2.0-39849087850 10.1007/s10620-007-9934-x (Pubitemid 351317087)
3. Villanueva A.; Chiang D. Y.; Newell P.; Peix J.; Thung S.; Alsinet C.; Tovar V.; Roayaie S.; Minguez B.; Sole M.; Battiston C.; van Laarhoven S.; Fiel M. I.; di Feo A.; Hoshida Y.; Yea S.; Toffanin S.; Ramos A.; Martignetti J. A.; Mazzaferro V.; Bruix J.; Waxman S.; Schwartz M.; Meyerson M.; Friedman S. L.; Llovet J. M.; Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008 135 6 1972.e1 1983.e11 2-s2.0-57349087153 10.1053/j.gastro.2008.08.008
4. Hay N.; Sonenberg N.; Upstream and downstream of mTOR. Genes and Development 2004 18 16 1926 1945 2-s2.0-4043171462 10.1101/gad.1212704 (Pubitemid 39071573)
5. Sancak Y.; Thoreen C. C.; Peterson T. R.; Lindquist R. A.; Kang S. A.; Spooner E.; Carr S. A.; Sabatini D. M.; PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Molecular Cell 2007 25 6 903 915 2-s2.0-33947264077 10.1016/j.molcel.2007.03.003 (Pubitemid 46436534)
6. Haar E. V.; Lee S.-I.; Bandhakavi S.; Griffin T. J.; Kim D.-H.; Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nature Cell Biology 2007 9 3 316 323 2-s2.0-33847397874 10.1038/ncb1547 (Pubitemid 46344611)
7. Loewith R.; Jacinto E.; Wullschleger S.; Lorberg A.; Crespo J. L.; Bonenfant D.; Oppliger W.; Jenoe P.; Hall M. N.; Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell 2002 10 3 457 468 2-s2.0-0036753494 10.1016/S1097-2765(02)00636-6 (Pubitemid 35284167)
8. Sarbassov D. D.; Ali S. M.; Kim D.-H.; Guertin D. A.; Latek R. R.; Erdjument-Bromage H.; Tempst P.; Sabatini D. M.; Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology 2004 14 14 1296 1302 2-s2.0-3342895823 10.1016/j.cub.2004.06.054 (Pubitemid 38991819)
9. Jacinto E.; Loewith R.; Schmidt A.; Lin S.; Rüegg M. A.; Hall A.; Hall M. N.; Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology 2004 6 11 1122 1128 2-s2.0-7944235758 10.1038/ncb1183 (Pubitemid 39468014)
10. Yip C. K.; Murata K.; Walz T.; Sabatini D. M.; Kang S. A.; Structure of the human mTOR complex I and its implications for rapamycin inhibition. Molecular Cell 2010 38 5 768 774 2-s2.0-77953091045 10.1016/j.molcel.2010.05.017
11. Kim D.-H.; Sarbassov D. D.; Ali S. M.; King J. E.; Latek R. R.; Erdjument-Bromage H.; Tempst P.; Sabatini D. M.; mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002 110 2 163 175 2-s2.0-0037178786 10.1016/S0092-8674(02)00808-5 (Pubitemid 34876545)
12. Sarbassov D. D.; Ali S. M.; Sengupta S.; Sheen J.-H.; Hsu P. P.; Bagley A. F.; Markhard A. L.; Sabatini D. M.; Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell 2006 22 2 159 168 2-s2.0-33646023695 10.1016/j.molcel.2006.03.029
13. Hara K.; Yonezawa K.; Kozlowski M. T.; Sugimoto T.; Andrabi K.; Weng Q.-P.; Kasuga M.; Nishimoto I.; Avruch J.; Regulation of eIF-4E BP1 phosphorylation by mTOR. Journal of Biological Chemistry 1997 272 42 26457 26463 2-s2.0-0030716488 10.1074/jbc.272.42.26457 (Pubitemid 27458864)
14. Hsieh A. C.; Costa M.; Zollo O.; Davis C.; Feldman M. E.; Testa J. R.; Meyuhas O.; Shokat K. M.; Ruggero D.; Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 2010 17 3 249 261 2-s2.0-77649286736 10.1016/j.ccr.2010.01.021
15. Shaw R. J.; Bardeesy N.; Manning B. D.; Lopez L.; Kosmatka M.; DePinho R. A.; Cantley L. C.; The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004 6 1 91 99 2-s2.0-3142594193 10.1016/j.ccr.2004.06. 007 (Pubitemid 38903165)
16. Corradetti M. N.; Inoki K.; Bardeesy N.; DePinho R. A.; Guan K.-L.; Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes and Development 2004 18 13 1533 1538 2-s2.0-3042818799 10.1101/gad.1199104 (Pubitemid 38868905)
17. Pene F.; Claessens Y.-E.; Muller O.; Viguié F.; Mayeux P.; Dreyfus F.; Lacombe C.; Bouscary D.; Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002 21 43 6587 6597 2-s2.0-0037179847 10.1038/sj.onc.1205923 (Pubitemid 35177037)
18. Hill M. M.; Hemmings B. A.; Inhibition of protein kinase B/Akt: implications for cancer therapy. Pharmacology and Therapeutics 2002 93 2-3 243 251 2-s2.0-0035990924 10.1016/S0163-7258(02)00193-6 (Pubitemid 34615565)
19. Martin D. E.; Hall M. N.; The expanding TOR signaling network. Current Opinion in Cell Biology 2005 17 2 158 166 2-s2.0-15044350668 10.1016/j.ceb.2005.02.008 (Pubitemid 40380939)
20. Hara K.; Yonezawa K.; Weng Q.-P.; Kozlowski M. T.; Belham C.; Avruch J.; Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. Journal of Biological Chemistry 1998 273 34 14484 14494 2-s2.0-0032555566 (Pubitemid 28319170)
21. Chiu M.; Tardito S.; Barilli A.; Bianchi M. G.; Dall'Asta V.; Bussolati O.; Glutamine stimulates mTORC1 independent of the cell content of essential amino acids. Amino Acids 2012 43 2561 2567 2-s2.0-84860570686 10.1007/s00726-012-1312-0
22. Sancak Y.; Peterson T. R.; Shaul Y. D.; Lindquist R. A.; Thoreen C. C.; Bar-Peled L.; Sabatini D. M.; The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008 320 5882 1496 1501 2-s2.0-45849105156 10.1126/science.1157535 (Pubitemid 351929429)
23. Kim E.; Goraksha-Hicks P.; Li L.; Neufeld T. P.; Guan K.-L.; Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biology 2008 10 8 935 945 2-s2.0-48649085816 10.1038/ncb1753
24. Duran R. V.; Oppliger W.; Robitaille A. M.; Glutaminolysis activates Rag-mTORC1 signaling. Molecular Cell 2012 47 349 358
25. Guo H.; Zhou T.; Jiang D.; Cuconati A.; Xiao G.-H.; Block T. M.; Guo J.-T.; Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-Akt signal transduction pathway. Journal of Virology 2007 81 18 10072 10080 2-s2.0-35348858953 10.1128/JVI.00541-07 (Pubitemid 350067711)
26. Wang W.; London W. T.; Feitelson M. A.; Hepatitis B x antigen in hepatitis B virus carrier patients with liver cancer. Cancer Research 1991 51 18 4971 4977 2-s2.0-0026425628
27. Wang H.-C.; Wu H.-C.; Chen C.-F.; Fausto N.; Lei H.-Y.; Su I.-J.; Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific Pre-S mutants that may induce endoplasmic reticulum stress. The American Journal of Pathology 2003 163 6 2441 2449 2-s2.0-0345707640 (Pubitemid 37466485)
28. Yang J.-C.; Teng C.-F.; Wu H.-C.; Tsai H.-W.; Chuang H.-C.; Tsai T.-F.; Hsu Y.-H.; Huang W.; Wu L.-W.; Su I.-J.; Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis. Hepatology 2009 49 6 1962 1971 2-s2.0-68949091981 10.1002/hep.22889
29. Teng C.-F.; Wu H.-C.; Tsai H.-W.; Shiah H.-S.; Huang W.; Su I.-J.; Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy. Hepatology 2011 54 4 1199 1207 2-s2.0-80053331166 10.1002/hep.24529
30. Sezgin Goksu S.; Bilal S.; Coskun H. S.; Hepatitis B reactivation related to everolimus. World Journal of Hepatology 2013 5 43 45
31. Neuveut C.; Wei Y.; Buendia M. A.; Mechanisms of HBV-related hepatocarcinogenesis. Journal of Hepatology 2010 52 4 594 604 2-s2.0-77949654113 10.1016/j.jhep.2009.10.033
32. Wang P.; Guo Q. S.; Wang Z. W.; Qian H. X.; HBx induces HepG-2 cells autophagy through PI3K/Akt-mTOR pathway. Molecular and Cellular Biochemistry 2013 372 161 168
33. Yen C. J.; Lin Y. J.; Yen C. S.; Hepatitis B virus X protein upregulates mTOR signaling through IKKbeta to increase cell proliferation and VEGF production in hepatocellular carcinoma. PLoS ONE 2012 7 e41931
34. Xu X.; Fan Z.; Kang L.; Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. The Journal of Clinical Investigation 2013 123 630 645
35. Shepard C. W.; Finelli L.; Alter M. J.; Global epidemiology of hepatitis C virus infection. The Lancet Infectious Diseases 2005 5 9 558 567 2-s2.0-23944506014 10.1016/S1473-3099(05)70216-4 (Pubitemid 41196755)
36. He Y.; Nakao H.; Tan S.-L.; Polyak S. J.; Neddermann P.; Vijaysri S.; Jacobs B. L.; Katze M. G.; Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase. Journal of Virology 2002 76 18 9207 9217 2-s2.0-0036721468 10.1128/JVI.76.18.9207-9217.2002 (Pubitemid 34919879)
37. Peng L.; Liang D.; Tong W.; Li J.; Yuan Z.; Hepatitis C virus NS5A activates the mammalian target of rapamycin (mTOR) pathway, contributing to cell survival by disrupting the interaction between FK506-binding protein 38 (FKBP38) and mTOR. Journal of Biological Chemistry 2010 285 27 20870 20881 2-s2.0-77954227028 10.1074/jbc.M110.112045
38. Shrivastava S.; Bhanja Chowdhury J.; Steele R.; Ray R.; Ray R. B.; Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. Journal of Virology 2012 86 8705 8712
39. Wang J.; Tong W.; Zhang X.; Chen L.; Yi Z.; Pan T.; Hu Y.; Xiang L.; Yuan Z.; Hepatitis C virus non-structural protein NS5A interacts with FKBP38 and inhibits apoptosis in Huh7 hepatoma cells. FEBS Letters 2006 580 18 4392 4400 2-s2.0-33746367134 10.1016/j.febslet.2006.07.002 (Pubitemid 44118256)
40. Ishida H.; Li K.; Yi M.; Lemon S. M.; p21-activated kinase 1 is activated through the mammalian target of rapamycin/p70 S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. Journal of Biological Chemistry 2007 282 16 11836 11848 2-s2.0-34249734825 10.1074/jbc.M610106200 (Pubitemid 47100711)
41. Sahin F.; Kannangai R.; Adegbola O.; Wang J.; Su G.; Torbenson M.; mTOR and P70 S6 kinase expression in primary liver neoplasms. Clinical Cancer Research 2004 10 24 8421 8425 2-s2.0-11144236505 10.1158/1078-0432.CCR-04-0941 (Pubitemid 40053405)
42. Zhou L.; Huang Y.; Li J.; Wang Z.; The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Medical Oncology 2010 27 2 255 261 2-s2.0-77953743694 10.1007/s12032-009-9201-4
43. Wouters B. G.; Koritzinsky M.; Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nature Reviews Cancer 2008 8 11 851 864 2-s2.0-54549089738 10.1038/nrc2501
44. Sengupta S.; Peterson T. R.; Sabatini D. M.; Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular Cell 2010 40 2 310 322 2-s2.0-78649348967 10.1016/j.molcel.2010.09.026
45. Weng Q.; Zhang J.; Cao J.; Xia Q.; Wang D.; Hu Y.; Sheng R.; Wu H.; Zhu D.; Zhu H.; He Q.; Yang B.; Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1 α expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells. Investigational New Drugs 2011 29 6 1177 1187 2-s2.0-84856064603
46. Land S. C.; Tee A. R.; Hypoxia-inducible factor 1 α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. Journal of Biological Chemistry 2007 282 28 20534 20543 2-s2.0-34547134517 10.1074/jbc.M611782200 (Pubitemid 47100043)
47. Ravikumar B.; Vacher C.; Berger Z.; Davies J. E.; Luo S.; Oroz L. G.; Scaravilli F.; Easton D. F.; Duden R.; O'Kane C. J.; Rubinsztein D. C.; Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genetics 2004 36 6 585 595 2-s2.0-2642586352 10.1038/ng1362 (Pubitemid 38715985)
48. Qu X.; Yu J.; Bhagat G.; Furuya N.; Hibshoosh H.; Troxel A.; Rosen J.; Eskelinen E.-L.; Mizushima N.; Ohsumi Y.; Cattoretti G.; Levine B.; Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. Journal of Clinical Investigation 2003 112 12 1809 1820 2-s2.0-9144240441 10.1172/JCI200320039 (Pubitemid 38063704)
49. Wendel H.-G.; Silva R. L. A.; Malina A.; Mills J. R.; Zhu H.; Ueda T.; Watanabe-Fukunaga R.; Fukunaga R.; Teruya-Feldstein J.; Pelletier J.; Lowe S. W.; Dissecting eIF4E action in tumorigenesis. Genes and Development 2007 21 24 3232 3237 2-s2.0-37249042829 10.1101/gad.1604407 (Pubitemid 350277750)
50. Guertin D. A.; Stevens D. M.; Saitoh M.; Kinkel S.; Crosby K.; Sheen J.-H.; Mullholland D. J.; Magnuson M. A.; Wu H.; Sabatini D. M.; mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009 15 2 148 159 2-s2.0-58649114084 10.1016/j.ccr.2008.12.017
51. Hietakangas V.; Cohen S. M.; TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer 2008 8, article 282 2-s2.0-54049100759 10.1186/1471-2407-8-282
52. Vinciguerra M.; Veyrat-Durebex C.; Moukil M. A.; Rubbia-Brandt L.; Rohner-Jeanrenaud F.; Foti M.; PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology 2008 134 1 268 280 2-s2.0-37349083834 10.1053/j.gastro.2007.10. 010 (Pubitemid 350309315)
53. Calvisi D. F.; Wang C.; Ho C.; Ladu S.; Lee S. A.; Mattu S.; Destefanis G.; Delogu S.; Zimmermann A.; Ericsson J.; Brozzetti S.; Staniscia T.; Chen X.; Dombrowski F.; Evert M.; Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 2011 140 3 1071 1083 2-s2.0-79952312698 10.1053/j.gastro.2010. 12.006
54. Nakanishi K.; Sakamoto M.; Yamasaki S.; Todo S.; Hirohashi S.; Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer 2005 103 2 307 312 2-s2.0-12344289067 10.1002/cncr.20774 (Pubitemid 40129290)
55. Düvel K.; Yecies J. L.; Menon S.; Raman P.; Lipovsky A. I.; Souza A. L.; Triantafellow E.; Ma Q.; Gorski R.; Cleaver S.; Vander Heiden M. G.; MacKeigan J. P.; Finan P. M.; Clish C. B.; Murphy L. O.; Manning B. D.; Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular Cell 2010 39 2 171 183 2-s2.0-77955483125 10.1016/j.molcel.2010.06.022
56. Porstmann T.; Santos C. R.; Griffiths B.; Cully M.; Wu M.; Leevers S.; Griffiths J. R.; Chung Y.-L.; Schulze A.; SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metabolism 2008 8 3 224 236 2-s2.0-50049116472 10.1016/j.cmet.2008.07.007
57. Menendez J. A.; Lupu R.; Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Reviews Cancer 2007 7 10 763 777 2-s2.0-34748912615 10.1038/nrc2222 (Pubitemid 47469806)
58. van de Sande T.; Roskams T.; Lerut E.; Joniau S.; v an Poppel H.; Verhoeven G.; Swinnen J. V.; High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB. The Journal of Pathology 2005 206 2 214 219 2-s2.0-19944398464 10.1002/path.1760 (Pubitemid 40754025)
59. van de Sande T.; de Schrijver E.; Heyns W.; Verhoeven G.; Swinnen J. V.; Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Research 2002 62 3 642 646 2-s2.0-0036469122 (Pubitemid 34126933)
60. Evert M.; Calvisi D. F.; Evert K.; de Murtas V.; Gasparetti G.; Mattu S.; Destefanis G.; Ladu S.; Zimmermann A.; Delogu S.; Thiel S.; Thiele A.; Ribback S.; Dombrowski F.; V-AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin activation induces a module of metabolic changes contributing to growth in insulin-induced hepatocarcinogenesis. Hepatology 2012 55 5 1473 1484 2-s2.0-84859978328 10.1002/hep.25600
61. Chaneton B.; Gottlieb E.; Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends in Biochemical Sciences 2012 37 309 316
62. Dombrauckas J. D.; Santarsiero B. D.; Mesecar A. D.; Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 2005 44 27 9417 9429 2-s2.0-21844468220 10.1021/bi0474923 (Pubitemid 40962040)
63. Mazurek S.; Pyruvate kinase type M2: a key regulator within the tumour metabolome and a tool for metabolic profiling of tumours. Oncogenes Meet Metabolism 2008 Springer 99 124
64. Yang W.; Xia Y.; Hawke D.; PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2012 150 685 696
65. Luo W.; Hu H.; Chang R.; Zhong J.; Knabel M.; O'Meally R.; Cole R. N.; Pandey A.; Semenza G. L.; Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011 145 5 732 744 2-s2.0-79957567239 10.1016/j.cell.2011.03.054
66. Gordan J. D.; Thompson C. B.; Simon M. C.; HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007 12 2 108 113 2-s2.0-34547580590 10.1016/j.ccr.2007.07.006 (Pubitemid 47199124)
67. West M. J.; Stoneley M.; Willis A. E.; Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway. Oncogene 1998 17 6 769 780 2-s2.0-0032514376 (Pubitemid 28412498)
68. Hudes G. R.; Berkenblit A.; Feingold J.; Atkins M. B.; Rini B. I.; Dutcher J.; Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma. Seminars in Oncology 2009 36 supplement 3 S26 S36 2-s2.0-72049097131 10.1053/j.seminoncol.2009.10.013
69. Motzer R. J.; Escudier B.; Oudard S.; Hutson T. E.; Porta C.; Bracarda S.; Grünwald V.; Thompson J. A.; Figlin R. A.; Hollaender N.; Urbanowitz G.; Berg W. J.; Kay A.; Lebwohl D.; Ravaud A.; Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. The Lancet 2008 372 9637 449 456 2-s2.0-48649107474 10.1016/S0140-6736(08)61039-9
70. Yao J. C.; Shah M. H.; Ito T.; Bohas C. L.; Wolin E. M.; van Cutsem E.; Hobday T. J.; Okusaka T.; Capdevila J.; de Vries E. G. E.; Tomassetti P.; Pavel M. E.; Hoosen S.; Haas T.; Lincy J.; Lebwohl D.; Öberg K.; Everolimus for advanced pancreatic neuroendocrine tumors. The New England Journal of Medicine 2011 364 6 514 523 2-s2.0-79851500081 10.1056/NEJMoa1009290
71. Krueger D. A.; Care M. M.; Holland K.; Agricola K.; Tudor C.; Mangeshkar P.; Wilson K. A.; Byars A.; Sahmoud T.; Franz D. N.; Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. The New England Journal of Medicine 2010 363 19 1801 1811 2-s2.0-78049510428 10.1056/NEJMoa1001671
72. Baselga J.; Campone M.; Piccart M.; Burris H. A. III, Rugo H. S.; Sahmoud T.; Noguchi S.; Gnant M.; Pritchard K. I.; Lebrun F.; Beck J. T.; Ito Y.; Yardley D.; Deleu I.; Perez A.; Bachelot T.; Vittori L.; Xu Z.; Mukhopadhyay P.; Lebwohl D.; Hortobagyi G. N.; Everolimus in postmenopausal hormone-receptor- positive advanced breast cancer. The New England Journal of Medicine 2012 366 6 520 529 2-s2.0-84856777655 10.1056/NEJMoa1109653
73. Semela D.; Piguet A.-C.; Kolev M.; Schmitter K.; Hlushchuk R.; Djonov V.; Stoupis C.; Dufour J.-F.; Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. Journal of Hepatology 2007 46 5 840 848 2-s2.0-34047118033 10.1016/j.jhep.2006.11.021 (Pubitemid 46529039)
74. Kelley R. K.; Nimeiri H. S.; Munster P. N.; Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates. Annals of Oncology 2013 24 1900 1907
75. Finn R. S.; Poon R. T.; Yau T.; Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. Journal of Hepatology 2013 59 6 1271 1277 10.1016/j.jhep.2013.07.029
76. Shiah H. S.; Chen C. Y.; Dai C. Y.; Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Alimentary Pharmacology & Therapeutics 2013 37 62 73
77. Rizell M.; Andersson M.; Cahlin C.; Hafström L.; Olausson M.; Lindnér P.; Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. International Journal of Clinical Oncology 2008 13 1 66 70 2-s2.0-40149098824 10.1007/s10147-007-0733-3 (Pubitemid 351326289)
78. Huynh H.; Chow P. K. H.; Palanisamy N.; Salto-Tellez M.; Goh B. C.; Lee C. K.; Somani A.; Lee H. S.; Kalpana R.; Yu K.; Tan P. H.; Wu J.; Soong R.; Lee M. H.; Hor H.; Soo K. C.; Toh H. C.; Tan P.; Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. Journal of Hepatology 2008 49 1 52 60 2-s2.0-44649202112 10.1016/j.jhep.2008.02.022
79. Tam K. H.; Yang Z. F.; Lau C. K.; Lam C. T.; Pang R. W. C.; Poon R. T. P.; Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. Cancer Letters 2009 273 2 201 209 2-s2.0-57349106607 10.1016/j.canlet.2008.08. 018
80. Piguet A.-C.; Semela D.; Keogh A.; Wilkens L.; Stroka D.; Stoupis C.; St-Pierre M. V.; Dufour J.-F.; Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. Journal of Hepatology 2008 49 1 78 87 2-s2.0-44649105082 10.1016/j.jhep.2008.03.024
81. Bu X.; Le C.; Jia F.; Guo X.; Zhang L.; Zhang B.; Wu M.; Wei L.; Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells. Cancer Biology and Therapy 2008 7 3 392 396 2-s2.0-45349106007 (Pubitemid 351847053)
82. Zhou Q.; Lui V. W. Y.; Lau C. P. Y.; Cheng S. H.; Ng M. H. L.; Cai Y.; Chan S. L.; Yeo W.; Sustained antitumor activity by co-targeting mTOR and the microtubule with temsirolimus/vinblastine combination in hepatocellular carcinoma. Biochemical Pharmacology 2012 83 9 1146 1158 2-s2.0-84858077469 10.1016/j.bcp.2012.01.013
83. Piguet A.-C.; Semela D.; Keogh A.; Wilkens L.; Stroka D.; Stoupis C.; St-Pierre M. V.; Dufour J.-F.; Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. Journal of Hepatology 2008 49 1 78 87 2-s2.0-44649105082 10.1016/j.jhep.2008.03.024
84. VanderWeele D. J.; Zhou R.; Rudin C. M.; Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Molecular Cancer Therapeutics 2004 3 12 1605 1613 2-s2.0-12344288380 (Pubitemid 40136716)
85. Wang C.; Gao D.; Guo K.; Kang X.; Jiang K.; Sun C.; Li Y.; Sun L.; Shu H.; Jin G.; Sun H.; Wu W.; Liu Y.; Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model. BMC Cancer 2012 12, article 166 2-s2.0-84860537456 10.1186/1471-2407-12- 166
86. Altmeyer A.; Josset E.; Denis J. M.; The mTOR inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy. International Journal of Oncology 2012 41 1381 1386
87. Soni A.; Akcakanat A.; Singh G.; Luyimbazi D.; Zheng Y.; Kim D.; Gonzalez-Angulo A.; Meric-Bernstam F.; eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Molecular Cancer Therapeutics 2008 7 7 1782 1788 2-s2.0-51049104528 10.1158/1535-7163.MCT-07-2357
88. Masuda M.; Shimomura M.; Kobayashi K.; Kojima S.; Nakatsura T.; Growth inhibition by NVP-BEZ235, a dual PI3K/mTOR inhibitor, in hepatocellular carcinoma cell lines. Oncology Reports 2011 26 5 1273 1279 2-s2.0-80053134885 10.3892/or.2011.1370
89. Thomas H. E.; Mercer C. A.; Carnevalli L. S.; mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Science Translational Medicine 2012 4 139ra84
90. Gedaly R.; Angulo P.; Hundley J.; Daily M. F.; Chen C.; Koch A.; Mark Evers B.; PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Research 2010 30 12 4951 4958 2-s2.0-78751513089