The Journal of Korean Medicine (대한한의학회지)

The Society of Korean Medicine (대한한의학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of mTOR signaling pathway by aqueous extract of Siberian ginseng

  • Received : 2017.03.30
  • Accepted : 2017.06.15
  • Published : 2017.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objectives: This study evaluated the effect of aqueous extract from roots of Siberian ginseng on mTORC1 pathway. Methods: mTORC1 activity was measured by the phosphorylation status of p70 S6 kinase (S6K) in HeLa cells as well as the brain, liver and muscle tissues in diabetic db/db mice. Autophagy induction after the treatment of Siberian ginseng extract was evaluated by monitoring the conversion of cytoplasmic LC3I into lipidated LC3II in cultured human HeLa GFP-LC3 cells. Cell cycle analysis was performed in HeLa cells treated with Siberian ginseng using flow cytometry. Results: Among >2,800 plant products used for oriental medicine, Siberian ginseng was found to inhibit mTORC1 to phosphorylate S6 kinsase (S6K) in HeLa cells as well as the brain, liver and muscle tissues in diabetic db/db mice. Siberian ginseng-mediated mTORC1 activity was reversible unlike the prolonged suppression of mTORC1 by rapamycin when HeLa cells were grown in fresh media after the removal of the inhibitors. Siberian ginseng extract at concentrations to inhibit mTORC1 was not overly cytotoxic in cultured HeLa cells whereas rapamycin was obviously cytotoxic. The conversion of cytoplasmic LCI into lipidated LCII was increased by fivefold in HeLa GFP-LC3 cells treated with Siberian ginseng extract. Progression of cell cycle was attenuated at G2/M phase by the treatment of Siberian ginseng extract. Conclusions: These results suggest that the aqueous extract of Siberian ginseng possibly plays a good therapeutic role in various diseases involving mTORC1 signaling.

Keywords

References

  1. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006; 124:471-84. https://doi.org/10.1016/j.cell.2006.01.016
  2. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122:3589-94. https://doi.org/10.1242/jcs.051011
  3. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008;27:1919-31. https://doi.org/10.1038/emboj.2008.119
  4. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007;12(4):487-502. https://doi.org/10.1016/j.devcel.2007.03.020
  5. Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem. 1997;272:26457-63. https://doi.org/10.1074/jbc.272.42.26457
  6. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA. 1998;95: 1432-7. https://doi.org/10.1073/pnas.95.4.1432
  7. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 2005;146:1473-81. https://doi.org/10.1210/en.2004-0921
  8. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149: 274-93. https://doi.org/10.1016/j.cell.2012.03.017
  9. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1): 21-35. https://doi.org/10.1038/nrm3025
  10. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey k, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-5. https://doi.org/10.1038/nature08221
  11. Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305-14. https://doi.org/10.1038/ncb1975
  12. Metcalfe SM, Canman CE, Milner J, Morris RE, Goldman S, Kastan MB. Rapamycin and p53 act on different pathways to induce G1 arrest in mammalian cells. Oncogene. 1997;15:1635-42. https://doi.org/10.1038/sj.onc.1201341
  13. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2010;1804(3):433-9. https://doi.org/10.1016/j.bbapap.2009.12.001
  14. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671-88. https://doi.org/10.1038/nrd2062
  15. Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int. 1996;49(1):209-16. https://doi.org/10.1038/ki.1996.28
  16. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today. 2007; 12(3-4):112-24. https://doi.org/10.1016/j.drudis.2006.12.008
  17. Hille U, Soergel P, Makowski L, Dork-Bousset T, Hillemanns P. Lymphedema of the breast as a symptom of internal diseases or side effect of mTOR inhibitors. Lymphat Res Biol. 2012;10(2): 63-73. https://doi.org/10.1089/lrb.2011.0025
  18. Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with mammalian target of rapamycin inhibitors. Clin J Oncol Nurs. 2011;15(5):E83-9. https://doi.org/10.1188/11.CJON.E83-E89
  19. Skrzypek J, Krause W. Azoospermia in a renal transplant recipient during sirolimus (rapamycin) treatment. Andrologia. 2007;39(5):198-9. https://doi.org/10.1111/j.1439-0272.2007.00787.x
  20. Huang L, Zhao H, Huang B, Zheng C, Peng W, Qin L. Acanthopanax senticosus: review of botany, chemistry and pharmacology. Pharmazie. 2011;66(2):83-97.
  21. Zhu HS, Yang XL, Wang LB, Zhao DX, Chen L. Effects of extracts from sporoderm-broken spores of Ganoderma lucidum on HeLa cells. Cell Biol Toxicol. 2000;16:201-6. https://doi.org/10.1023/A:1007663006548
  22. Mizushima N, Klionsky DJ. Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr. 2007;27:19-40. https://doi.org/10.1146/annurev.nutr.27.061406.093749
  23. Suk J, Kwak SS, Lee JH, Choi JH, Lee SH, Lee DH, et al. Alkaline stress-induced autophagy is mediated by mTORC1 inactivation. J Cell Biochem. 2011;112(9):2566-73. https://doi.org/10.1002/jcb.23181
  24. Ramirez-Valle F, Badura ML, Braunstein S, Narasimhan M, Schneider RJ. Mitotic raptor promotes mTORC1 activity, G2/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation. Mol Cell Biol. 2010;30(13):3151-64. https://doi.org/10.1128/MCB.00322-09
  25. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65(16):7052-8. https://doi.org/10.1158/0008-5472.CAN-05-0917
  26. Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci USA. 2008;105(45):17414-9. https://doi.org/10.1073/pnas.0809136105
  27. Breuleux M, Klopfenstein N, Stephan C, Doughty CA, Barys L, Maira SM, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009;8(4):742-53. https://doi.org/10.1158/1535-7163.MCT-08-0668
  28. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261-74. https://doi.org/10.1016/j.cell.2007.06.009
  29. Watanabe R, Wei L, Huang J. mTOR signaling, function, novel inhibitors, and therapeutic targets. J Nucl Med. 2011;52(4):497-500.
  30. Mori H, Inoki K, Masutani K, Wakabayashi Y, Komai K, Nakagawa R, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun. 2009;384(4): 471-5. https://doi.org/10.1016/j.bbrc.2009.04.136
  31. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992-2003. https://doi.org/10.1091/mbc.e08-12-1249
  32. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27-42. https://doi.org/10.1016/j.cell.2007.12.018
  33. Wang X, Proud CG. Nutrient control of TORC1, a cell-cyle regulator. Trends Cell Biol. 2009; 19(6):260-7. https://doi.org/10.1016/j.tcb.2009.03.005