Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2)

Diabetologia

Volumn 55, Issue 5, 2012, Pages 1355-1365

  Barlow, A D ^a   Xie, J ^a   Moore, C E ^a   Campbell, S C ^b   Shaw, J A M ^b   Nicholson, M L ^a   Herbert, T P ^a  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Apoptosis; Beta cell; Diabetes mellitus; GSIS; Islet; Islet transplantation; MTOR; MTORC2; PKB; Rapamycin; RICTOR

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PROTEIN KINASE B; RAPAMYCIN; RAPAMYCIN INSENSITIVE COMPANION OF TARGET OF RAPAMYCIN; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CELL DEATH; CELL PROTECTION; CELL VIABILITY; CONTROLLED STUDY; CYTOTOXICITY; ENZYME ASSAY; ENZYME INHIBITION; ENZYME LINKED IMMUNOSORBENT ASSAY; ENZYME SYNTHESIS; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; INTRACELLULAR SIGNALING; MALE; NONHUMAN; PANCREAS ISLET BETA CELL; PANCREAS ISLET CELL FUNCTION; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SYNTHESIS INHIBITION; RAT; RNA INTERFERENCE; WESTERN BLOTTING;

ANIMALS; CELL SURVIVAL; CELLS, CULTURED; FEMALE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; ISLETS OF LANGERHANS; MALE; PROTO-ONCOGENE PROTEINS C-AKT; RATS; RATS, SPRAGUE-DAWLEY; RNA, SMALL INTERFERING; SIGNAL TRANSDUCTION; SIROLIMUS; TRANS-ACTIVATORS; TRANSCRIPTION FACTORS;

EID: 84862528153     PISSN: 0012186X     EISSN: 14320428     Source Type: Journal    
DOI: 10.1007/s00125-012-2475-7     Document Type: Article

References (48)

1. Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343: 230-238
2. Ryan EA, Paty BW, Senior PA et al (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54: 2060-2069
3. Fabian MC, Lakey JR, Rajotte RV, Kneteman NM (1993) The efficacy and toxicity of rapamycin in murine islet transplantation. In vitro and in vivo studies. Transplantation 56: 1137-1142
4. Bell E, Cao X,Moibi JA et al (2003) Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes 52: 2731-2739
5. Zhang N, Su D, Qu S et al (2006) Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes 55: 2429-2436
6. Smith RN, Kent SC, Nagle J et al (2008) Pathology of an islet transplant 2 years after transplantation: evidence for a nonimmunological loss. Transplantation 86: 54-62
7. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12: 21-35
8. Xie J, Herbert TP (2011) The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic beta-cell mass: implications in the development of type-2 diabetes. Cell Mol Life Sci. doi: 10.1007/s00018-011-0874-4
9. 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: 1122-1128
10. Sarbassov DD, Ali SM, Sengupta S et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-168
11. Zeng Z, dos Sarbassov D, Samudio IJ et al (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109: 3509-3512
12. Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412: 179-190
13. Shigeyama Y, Kobayashi T, Kido Yet al (2008) Biphasic response of pancreatic beta cell mass to ablation of TSC2 in mice. Mol Cell Biol 28: 2971-2979
14. Rachdi L, Balcazar N, Osorio-Duque F et al (2008) Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci USA 105: 9250-9255
15. Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1- deficient mice. Nature 408: 994-997
16. Ruvinsky I, Sharon N, Lerer T et al (2005) Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 19: 2199-2211
17. Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA (2011) Rictor/ mTORC2 is essential for maintaining a balance between β-cell proliferation and cell size. Diabetes 60: 827-837
18. Thoreen CC, Kang SA, Chang JWet al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284: 8023-8032
19. Miyazaki J, Araki K, Yamato E et al (1990) Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127: 126-132
20. Moore CE, Xie J, Gomez E, Herbert TP (2009) Identification of cAMP-dependent kinase as a third in vivo ribosomal protein S6 kinase in pancreatic beta-cells. J Mol Biol 389: 480-494
21. Moore CE, Omikorede O, Gomez E, Willars GB, Herbert TP (2011) PERK activation at low glucose concentration is mediated by SERCA pump inhibition and confers preemptive cytoprotection to pancreatic beta-cells. Mol Endocrinol 25: 315-326
22. Huang GC, Zhao M, Jones P et al (2004) The development of new density gradient media for purifying human islets and islet-quality assessments. Transplantation 77: 143-145
23. Gomez E, Powell ML, Bevington A, Herbert TP (2008) A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochem J 410: 485-493
24. Xie J, Ponuwei GA, Moore CE, Willars GB, Tee AR, Herbert TP (2011) cAMP inhibits mammalian target of rapamycin complex-1 and ?2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity. Cell Signal 23: 1927-1935
25. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785-789
26. Jonkers FC, Henquin JC (2001) Measurements of cytoplasmic Ca2+ in islet cell clusters show that glucose rapidly recruits beta-cells and gradually increases the individual cell response. Diabetes 50: 540-550
27. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101
28. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27: 1919-1931
29. Facchinetti V, Ouyang W, Wei H et al (2008) The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27: 1932-1943
30. Desai NM, Goss JA, Deng S et al (2003) Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity? Transplantation 76: 1623-1625
31. Kohn AD, Takeuchi F, Roth RA (1996) Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271: 21920-21926
32. Alessi DR, James SR, Downes CP et al (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7: 261-269
33. Elghazi L, Bernal-Mizrachi E (2009) Akt and PTEN: beta-cell mass and pancreas plasticity. Trends Endocrinol Metab 20: 243-251
34. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ (2001) Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349-38352
35. Garofalo RS, Orena SJ, Rafidi K et al (2003) Severe diabetes, agedependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112: 197-208
36. Moore SF, Hunter RW, Hers I (2011) mTORC2 Protein-mediated protein kinase B (Akt) serine 473 phosphorylation is not required for Akt1 activity in human platelets. J Biol Chem 286: 24553-24560
37. Elghazi L, Balcazar N, Blandino-Rosano M et al (2010) Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells. Diabetes 59: 2390-2399
38. Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKcalpha, but not S6K1. Dev Cell 11: 859-871
39. Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23: 1515-1527
40. McDaniel ML,Marshall CA, Pappan KL, Kwon G (2002)Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. Diabetes 51: 2877-2885
41. Johnson JD, Ao Z, Ao P et al (2009) Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant 18: 833-845
42. Gomez E, Powell ML, Greenman IC, Herbert TP (2004) Glucosestimulated protein synthesis in pancreatic beta-cells parallels an increase in the availability of the translational ternary complex (eIF2-GTP.Met-tRNAi) and the dephosphorylation of eIF2 alpha. J Biol Chem 279: 53937-53946
43. Shimodahira M, Fujimoto S, Mukai E et al (2010) Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism. J Endocrinol 204: 37-46
44. Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, De Eckhoff (2002) Simvastatin induces activation of the serinethreonine protein kinase AKT and increases survival of isolated human pancreatic islets. Transplantation 74: 1063-1069
45. Wang Q, Li L, Xu E, Wong V, Rhodes C, Brubaker PL (2004) Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia 47: 478-487
46. Li L, El-Kholy W, Rhodes CJ, Brubaker PL (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48: 1339-1349
47. Favaro E, Miceli I, Bussolati B et al (2008) Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells: effects of pravastatin on the Akt survival pathway. Am J Pathol 173: 442-450
48. Shuai H, Zhang J, Zhang J et al (2011) Erythropoietin protects pancreatic beta-cell line NIT-1 cells against cytokine-induced apoptosis via phosphatidylinositol 3-kinase/Akt signaling. Endocr Res 36: 25-34