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Clinical and Translational Oncology

, Volume 9, Issue 8, pp 484–493 | Cite as

mTOR signaling in human cancer

  • J. AlbanellEmail author
  • A. Dalmases
  • A. Rovira
  • F. Rojo
Educational Series Green Series

Abstract

Inhibitors of mTOR, the mammalian target of rapamycin, have been extensively studied in clinical trials for cancer treatment. Results have been promising, mostly in certain lymphomas, but in solid tumours the results have been generally less encouraging. However, recent results, particularly in renal cell carcinoma, have provided renewed interest in the role of mTOR inhibitors in solid tumours. A rational, and potentially more successful, development of these agents (i.e., RAD001, temsirolimus and AP23573) likely relies in a deeper knowledge of mTOR signalling in cancer, both at the preclinical and clinical levels. These would allow a better selection of patients more likely to respond to the use of biologically active doses of the agents and the development of mechanistically based combinations with other agents. The goal of this review is to provide an update on the complex signalling of mTOR in cancer and on the biological effects of mTOR inhibitors in cancer cells.

Key words

mTOR Rapamycin RAD001 Temsirolimus AP23573 

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References

  1. 1.
    Manning BD (2004) Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167:399–403PubMedCrossRefGoogle Scholar
  2. 2.
    Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103:253–262PubMedCrossRefGoogle Scholar
  3. 3.
    Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945PubMedCrossRefGoogle Scholar
  4. 4.
    Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603PubMedCrossRefGoogle Scholar
  5. 5.
    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 123:569–580PubMedCrossRefGoogle Scholar
  6. 6.
    Scheper GC, van Kollenburg B, Hu J et al (2002) Phosphorylation of eukaryotic initiation factor 4E markedly reduces its aff inity for capped mRNA. J Biol Chem 277:3303–3309PubMedCrossRefGoogle Scholar
  7. 7.
    Mamane Y, Petroulakis E, Rong L et al (2004) eIF4E-from translation to transformation. Oncogene 23:3172–3179PubMedCrossRefGoogle Scholar
  8. 8.
    Gibbons JJ, Discafani C, Peterson R et al (2000) The effect of CCI-779, a novel macrolide antitumor agent, on the growth of human tumor cells in vitro and in nude mouse xenograft in vivo. Proc Am Assoc Cancer Res 40:301Google Scholar
  9. 9.
    Boulay A, Zumstein-Mecker S, Stephan C et al (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261PubMedCrossRefGoogle Scholar
  10. 10.
    Lane H, Tanaka C, Kovarik J et al (2003) Preclinical and clinical pharmakinetic/pharmacodynamic (PK/PD) modeling to help to define an optimal biological dose for the oral mTOR inhibitor, RAD001, in oncology. Proc Am Soc Clin Oncol 22: 2003 (abstr 951)Google Scholar
  11. 11.
    Clackson T, Metcalf C III, Rozamus LW et al (2002) Regression of tumor xenografts in mice after oral administration of AP23573, a novel mTOR inhibitor that induces tumor starvation. Proc Am Assoc Cancer Res 43:abstract LB95Google Scholar
  12. 12.
    Chiu MI, Katz H, Berlin V (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 91:12574–12578PubMedCrossRefGoogle Scholar
  13. 13.
    Perry J, Kleckner N (2003) The ATRs, ATMs, and TORs are giant HEAT repeat proteins. Cell 112:151–155PubMedCrossRefGoogle Scholar
  14. 14.
    Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484PubMedCrossRefGoogle Scholar
  15. 15.
    Keith CT, Schreiber SL (1995) PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270:50–51PubMedCrossRefGoogle Scholar
  16. 16.
    van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808PubMedCrossRefGoogle Scholar
  17. 17.
    Gao X, Pan D (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15:1383–1392PubMedCrossRefGoogle Scholar
  18. 18.
    Saucedo LJ, Gao X, Chiarelli DA et al (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5:566–571PubMedCrossRefGoogle Scholar
  19. 19.
    Garami A, Zwartkruis FJ, Nobukuni T et al (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466PubMedCrossRefGoogle Scholar
  20. 20.
    Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17: 1829–1834PubMedCrossRefGoogle Scholar
  21. 21.
    Chung J, Grammer TC, Lemon KP et al (1994) PDGF-and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 370:71–75PubMedCrossRefGoogle Scholar
  22. 22.
    Gingras J, Cabana T (1998) The development of synaptophysin-like immunoreactivity in the lumbosacral enlargement of the spinal cord of the opossum Monodelphis domestica. Brain Res Dev Brain Res 106:211–215PubMedCrossRefGoogle Scholar
  23. 23.
    Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319PubMedCrossRefGoogle Scholar
  24. 24.
    Podsypanina K, Lee RT, Politis C et al (2001) An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/-mice. Proc Natl Acad Sci U S A 98:10320–10325PubMedCrossRefGoogle Scholar
  25. 25.
    Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760–768PubMedCrossRefGoogle Scholar
  26. 26.
    Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280:33076–33082PubMedCrossRefGoogle Scholar
  27. 27.
    Nobukuni T, Joaquin M, Roccio M et al (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102: 14238–14243PubMedCrossRefGoogle Scholar
  28. 28.
    Proud CG (2004) The multifaceted role of mTOR in cellular stress responses. DNA Repair (Amst) 3:927–934CrossRefGoogle Scholar
  29. 29.
    Brugarolas JB, Vazquez F, Reddy A et al (2003) TSC2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell 4:147–158PubMedCrossRefGoogle Scholar
  30. 30.
    Kruppa J, Clemens MJ (1984) Differential kinetics of changes in the state of phosphorylation of ribosomal protein S6 and in the rate of protein synthesis in MPC 11 cells during tonicity shifts. EMBO J 3:95–100PubMedGoogle Scholar
  31. 31.
    O’shea C, Klupsch K, Choi S et al (2005) Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. EMBO J 24:1211–1221PubMedCrossRefGoogle Scholar
  32. 32.
    Wang L, Fraley CD, Faridi J et al (2003) Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells. Proc Natl Acad Sci U S A 100:11249–11254PubMedCrossRefGoogle Scholar
  33. 33.
    Ma L, Chen Z, Erdjument-Bromage H et al (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–193PubMedCrossRefGoogle Scholar
  34. 34.
    Roux PP, Ballif BA, Anjum R et al (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A 101:13489–13494PubMedCrossRefGoogle Scholar
  35. 35.
    Johannessen CM, Reczek EE, James MF et al (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A 102:8573–8578PubMedCrossRefGoogle Scholar
  36. 36.
    Constantinou C, Clemens MJ (2005) Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53. Oncogene 24:4839–4850PubMedCrossRefGoogle Scholar
  37. 37.
    Birchenall-Roberts MC, Fu T, Bang OS et al (2004) Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways. J Biol Chem 279:25605–25613PubMedCrossRefGoogle Scholar
  38. 38.
    Shin I, Yakes FM, Rojo F et al (2002) PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8:1145–1152PubMedCrossRefGoogle Scholar
  39. 39.
    Asano K, Vornlocher HP, Richter-Cook NJ et al (1997) Structure of cDNAs encoding human eukaryotic initiation factor 3 subunits. Possible roles in RNA binding and macromolecular assembly. J Biol Chem 272:27042–27052PubMedCrossRefGoogle Scholar
  40. 40.
    Castellvi J, Garcia A, Rojo F et al (2006) Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107:1801–1811PubMedCrossRefGoogle Scholar
  41. 41.
    Rojo F, Najera L, Lirola J et al (2007) 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin Cancer Res 13:81–89PubMedCrossRefGoogle Scholar
  42. 42.
    Bernal A, Kimbrell DA (2000) Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity. Proc Natl Acad Sci U S A 97:6019–6024PubMedCrossRefGoogle Scholar
  43. 43.
    Gingras AC, Raught B, Gygi SP et al (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852–2864PubMedCrossRefGoogle Scholar
  44. 44.
    Scheper GC, Proud CG (2002) Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur J Biochem 269:5350–5359PubMedCrossRefGoogle Scholar
  45. 45.
    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 102:8204–8209PubMedCrossRefGoogle Scholar
  46. 46.
    Schalm SS, Blenis J (2002) Identification of a conserved motif required for mTOR signaling. Curr Biol 12:632–639PubMedCrossRefGoogle Scholar
  47. 47.
    Shima H, Pende M, Chen Y et al (1998) Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 17:6649–6659PubMedCrossRefGoogle Scholar
  48. 48.
    Radimerski T, Montagne J, Rintelen F et al (2002) dS6K-regulated cell growth is dPKB/ dPI(3)K-independent, but requires dPDK1. Nat Cell Biol 4:251–255PubMedCrossRefGoogle Scholar
  49. 49.
    Radimerski T, Mini T, Schneider U et al (2000) Identification of insulin-induced sites of ribosomal protein S6 phosphorylation in Drosophila melanogaster. Biochemistry 39:5766–5774PubMedCrossRefGoogle Scholar
  50. 50.
    Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344PubMedCrossRefGoogle Scholar
  51. 51.
    Hara K, Yonezawa K, Weng QP et al (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273:14484–14494PubMedCrossRefGoogle Scholar
  52. 52.
    Rogers GW Jr, Komar AA, Merrick WC (2002) eIF4A: the godfather of the DEAD box helicases. Prog Nucleic Acid Res Mol Biol 72:307–331PubMedCrossRefGoogle Scholar
  53. 53.
    de Groot RP, Ballou LM, Sassone-Corsi P (1994) Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 79:81–91PubMedCrossRefGoogle Scholar
  54. 54.
    Raught B, Gingras AC, Gygi SP et al (2000) Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 19:434–444PubMedCrossRefGoogle Scholar
  55. 55.
    Browne GJ, Proud CG (2004) A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 24:2986–2997PubMedCrossRefGoogle Scholar
  56. 56.
    Fang P, Hwa V, Rosenfeld RG (2006) Interferongamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. Exp Cell Res 312:1229–1239PubMedCrossRefGoogle Scholar
  57. 57.
    Ishigaki Y, Li X, Serin G, Maquat LE (2001) Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106:607–617PubMedCrossRefGoogle Scholar
  58. 58.
    Eng C (2003) Constipation, polyps, or cancer? Let PTEN predict your future. Am J Med Genet A 122:315–322PubMedCrossRefGoogle Scholar
  59. 59.
    Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMedCrossRefGoogle Scholar
  60. 60.
    Teng DH, Hu R, Lin H et al (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225PubMedGoogle Scholar
  61. 61.
    Cheney IW, Johnson DE, Vaillancourt MT et al (1998) Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 58:2331–2334PubMedGoogle Scholar
  62. 62.
    Di Cristofano A, Kotsi P, Peng YF et al (1999) Impaired Fas response and autoimmunity in Pten+/-mice. Science 285:2122–2125PubMedCrossRefGoogle Scholar
  63. 63.
    Shioi T, McMullen JR, Kang PM et al (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22:2799–2809PubMedCrossRefGoogle Scholar
  64. 64.
    Samuels Y, Velculescu VE (2004) Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3:1221–1224PubMedGoogle Scholar
  65. 65.
    Dillon RL, White DE, Muller WJ (2007) The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene 26:1338–1345PubMedCrossRefGoogle Scholar
  66. 66.
    Jucker M, Sudel K, Horn S et al (2002) Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin’s lymphoma-derived cell line (CO). Leukemia 16:894–901PubMedCrossRefGoogle Scholar
  67. 67.
    Malik SN, Brattain M, Ghosh PM et al (2002) Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 8:1168–1171PubMedGoogle Scholar
  68. 68.
    Roy HK, Olusola BF, Clemens DL et al (2002) AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23:201–205PubMedCrossRefGoogle Scholar
  69. 69.
    Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–3997PubMedGoogle Scholar
  70. 70.
    van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808PubMedCrossRefGoogle Scholar
  71. 71.
    Adachi H, Igawa M, Shiina H et al (2003) Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. J Urol 170:601–604PubMedCrossRefGoogle Scholar
  72. 72.
    Kwiatkowski DJ (2003) Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol Ther 2:471–476PubMedGoogle Scholar
  73. 73.
    El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ (2003) Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361:1348–1349PubMedCrossRefGoogle Scholar
  74. 74.
    Topisirovic I, Ruiz-Gutierrez M, Borden KL (2004) Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res 64:8639–8642PubMedCrossRefGoogle Scholar
  75. 75.
    Avdulov S, Li S, Michalek V et al (2004) Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5:553–563PubMedCrossRefGoogle Scholar
  76. 76.
    Thornton S, Anand N, Purcell D, Lee J (2003) Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis. J Mol Med 81:536–548PubMedCrossRefGoogle Scholar
  77. 77.
    Li S, Takasu T, Perlman DM et al (2003) Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release. J Biol Chem 278:3015–3022PubMedCrossRefGoogle Scholar
  78. 78.
    Ruggero D, Montanaro L, Ma L et al (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10:484–486PubMedCrossRefGoogle Scholar
  79. 79.
    Oridate N, Kim HJ, Xu X, Lotan R (2005) Growth inhibition of head and neck squamous carcinoma cells by small interfering RNAs targeting eIF4E or cyclin D1 alone or combined with cisplatin. Cancer Biol Ther 4:318–323PubMedCrossRefGoogle Scholar
  80. 80.
    Graff JR, Zimmer SG (2003) Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin Exp Metastasis 20:265–273PubMedCrossRefGoogle Scholar
  81. 81.
    Culjkovic B, Topisirovic I, Skrabanek L et al (2005) eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3’UTR. J Cell Biol 169:245–256PubMedCrossRefGoogle Scholar
  82. 82.
    Lynch M, Fitzgerald C, Johnston KA et al (2004) Activated eIF4E-binding protein slows G1 progression and blocks transformation by cmyc without inhibiting cell growth. J Biol Chem 279:3327–3339PubMedCrossRefGoogle Scholar
  83. 83.
    Surace EI, Lusis E, Haipek CA, Gutmann DH (2004) Functional significance of S6K overexpression in meningioma progression. Ann Neurol 56:295–298PubMedCrossRefGoogle Scholar
  84. 84.
    Barlund M, Forozan F, Kononen J et al (2000) Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst 92:1252–1259PubMedCrossRefGoogle Scholar
  85. 85.
    Sehgal SN (1995) Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 17:660–665PubMedCrossRefGoogle Scholar
  86. 86.
    Campistol JM, Albanell J, Arns W et al (2007) Use of proliferation signal inhibitors in the management of post-transplant malignancies — clinical guidance. Nephrol Dial Transplant 22[Suppl 1]:i36–41PubMedCrossRefGoogle Scholar
  87. 87.
    Eng CP, Sehgal SN, Vezina C (1984) Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37:1231–1237Google Scholar
  88. 88.
    Seufferlein T, Rozengurt E (1996) Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 56:3895–3897PubMedGoogle Scholar
  89. 89.
    Choi J, Chen J, Schreiber SL, Clardy J (1996) Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273:239–242PubMedCrossRefGoogle Scholar
  90. 90.
    Cresta S, Tosi D, Sessa C et al (2007) Phase 1b study defining the optimal dosing combinations of the mTOR inhibitor AP23573 and Paclitaxel (PTX). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I.25:3509Google Scholar
  91. 91.
    Rubio-Viqueira B, Hidalgo M (2006) Targeting mTOR for cancer treatment. Curr Opin Investig Drugs 7:501–512PubMedGoogle Scholar
  92. 92.
    Tabernero J, Rojo F, Burris H et al (2005) A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings 23:3007Google Scholar
  93. 93.
    McMahon LP, Choi KM, Lin TA et al (2002) The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol Cell Biol 22:7428–7438PubMedCrossRefGoogle Scholar
  94. 94.
    Bader AG, Felts KA, Jiang N et al (2003) Y boxbinding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway. Proc Natl Acad Sci U S A 100:12384–12389PubMedCrossRefGoogle Scholar
  95. 95.
    Costa LF, Balcells M, Edelman ER et al (2006) Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-kappaB. Blood 107:285–292PubMedCrossRefGoogle Scholar
  96. 96.
    Costa LJ (2007) Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin’s lymphoma. Cancer Treat Rev 33:78–84PubMedCrossRefGoogle Scholar
  97. 97.
    Stephan S, Datta K, Wang E et al (2004) Effect of rapamycin alone and in combination with antiangiogenesis therapy in an orthotopic model of human pancreatic cancer. Clin Cancer Res 10:6993–7000PubMedCrossRefGoogle Scholar
  98. 98.
    Cross DA, Watt PW, Shaw M et al (1997) Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. FEBS Lett 406:211–215PubMedCrossRefGoogle Scholar
  99. 99.
    Zha J, Harada H, Yang E et al (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628PubMedCrossRefGoogle Scholar
  100. 100.
    Moumen A, Patane S, Porras A et al (2007) Met acts on Mdm2 via mTOR to signal cell survival during development. Development 134:1443–1451PubMedCrossRefGoogle Scholar
  101. 101.
    Easton JB, Kurmasheva RT, Houghton PJ (2006) IRS-1: auditing the effectiveness of mTOR inhibitors. Cancer Cell 9:153–155PubMedCrossRefGoogle Scholar
  102. 102.
    Yan H, Frost P, Shi Y et al (2006) Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 66:2305–2313PubMedCrossRefGoogle Scholar
  103. 103.
    Beuvink I, Boulay A, Fumagalli S et al (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120:747–759PubMedCrossRefGoogle Scholar
  104. 104.
    Guba M, von Breitenbuch P, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135PubMedCrossRefGoogle Scholar
  105. 105.
    Yu Y, Sato JD (1999) MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol 178:235–246PubMedCrossRefGoogle Scholar
  106. 106.
    Suhara T, Mano T, Oliveira BE, Walsh K (2001) Phosphatidylinositol 3-kinase/Akt signaling controls endothelial cell sensitivity to Fas-mediated apoptosis via regulation of FLICE-inhibitory protein (FLIP). Circ Res 89:13–19PubMedGoogle Scholar
  107. 107.
    Bruns CJ, Koehl GE, Guba M et al (2004) Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res 10:2109–2119PubMedCrossRefGoogle Scholar
  108. 108.
    Majumder PK, Febbo PG, Bikoff R et al (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601PubMedCrossRefGoogle Scholar
  109. 109.
    Mellado B, Gascon P (2006) Molecular biology of renal cell carcinoma. Clin Transl Oncol 8: 706–710PubMedCrossRefGoogle Scholar
  110. 110.
    Bellmunt J, Montagut C, Albiol S et al (2007) Present strategies in the treatment of metastatic renal cell carcinoma: an update on molecular targeting agents. BJU Int 99:274–280PubMedCrossRefGoogle Scholar
  111. 111.
    Garcia JA, Rini BI (2007) Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin 57:112–125PubMedCrossRefGoogle Scholar
  112. 112.
    deGraffenried LA, Friedrichs WE, Russell DH et al (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10:8059–8067PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2007

Authors and Affiliations

  • J. Albanell
    • 1
    • 2
    Email author
  • A. Dalmases
    • 2
  • A. Rovira
    • 1
    • 2
  • F. Rojo
    • 2
    • 3
  1. 1.Medical Oncology ServiceHospital del MarBarcelonaSpain
  2. 2.Experimental Therapy of Cancer Research Unit (URTEC)IMIM-Hospital del Mar. PRBBBarcelonaSpain
  3. 3.Department of PathologyHospital del Mar-IMASBarcelonaSpain

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