Skip to main content
SpringerLink
Log in

Akt/AMPK/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Vitamin E succinate (VES), a derivative of vitamin E, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing apoptotic cell death. The effects of VES on autophagy, an intricate programmed process which helps cells survive in some stressed situations by degrading some cytoplasmic material, are unclear. When human gastric cancer cells SCG-7901 were exposed to VES, both the level of microtubule-associated protein 1 light chain 3 and the yeast ATG6 homolog Beclin-1 increased, and related autophagy genes were activated, thereby suggesting that autophagy was induced by VES. We also observed that VES-induced autophagy was accompanied by the activation of AMP-activated protein kinases (AMPK). VES-induced autophagy decreased when AMPK was inhibited by using small interfering RNA (siRNA), thereby suggesting that VES-induced autophagy is mediated by AMPK. Moreover, further studies revealed that the decreased activity of mammalian target of rapamycin (mTOR) and its downstream targets P70S6K and 4EBP-1 were involved in VES-activated autophagy associated with AMPK activation. The experiments also showed that the activity of protein kinases B (Akt)-mTOR axis was inhibited by VES. VES-induced AMPK activation could be attenuated by Akt activation. Overall, our studies demonstrated that AMPK was involved in the VES-induced autophagy. Crosstalk exists between AMPK and the Akt/mTOR axis. The results elucidated the mechanism of VES-induced autophagy in human gastric cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108

    Article  PubMed  Google Scholar 

  2. Ohtsu A (2008) Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol 43(4):256–264

    Article  CAS  PubMed  Google Scholar 

  3. Huang X, Zhang Z, Jia L, Zhao Y, Zhang X, Wu K (2010) Endoplasmic reticulum stress contributes to vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. Cancer Lett 296(1):123–131

    Article  CAS  PubMed  Google Scholar 

  4. Wu K, Li Y, Zhao Y, Shan YJ, Xia W, Yu WP, Zhao L (2002) Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. World J Gastroenterol 8(6):982–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wu K, Zhao Y, Li GC, Yu WP (2004) c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells. World J Gastroenterol 10(8):1110–1114

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Israel K, Yu W, Sanders BG, Kline K (2000) Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis. Nutr Cancer 36(1):90–100

    Article  CAS  PubMed  Google Scholar 

  7. Neuzil J, Weber T, Gellert N, Weber C (2001) Selective cancer cell killing by α-tocopheryl succinate. Br J Cancer 84(1):87–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sahu SN, Edwards-Prasad J, Prasad KN (1988) Effect of alpha tocopheryl succinate on adenylate cyclase activity in murine neuroblastoma cells in culture. J Am Coll Nutr 7(4):285–293

    Article  CAS  PubMed  Google Scholar 

  9. Wu K, Zhao Y, Liu BH, Li Y, Liu F, Guo J, Yu WP (2002) RRR-alpha-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest. World J Gastroenterol 8(1):26–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu W, Israel K, Liao QY, Aldaz CM, Sanders BG, Kline K (1999) Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis. Cancer Res 59(4):953–961

    CAS  PubMed  Google Scholar 

  11. Zhang X, Peng X, Yu W, Hou S, Zhao Y, Zhang Z, Huang X, Wu K (2011) Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux. Cancer Lett 307(2):174–181

    Article  CAS  PubMed  Google Scholar 

  12. Bang OS, Park JH, Kang SS (2001) Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells. Biochem Biophys Res Commun 288(4):789–797

    Article  CAS  PubMed  Google Scholar 

  13. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16(7):966–975

    Article  CAS  PubMed  Google Scholar 

  14. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23(16):2891–2906

    Article  CAS  PubMed  Google Scholar 

  15. Klionsky DJ (2010) The autophagy connection. Dev Cell 19(1):11–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9(10):1102–1109

    Article  CAS  PubMed  Google Scholar 

  18. Geng J, Klionsky DJ (2008) The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep 9(9):859–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22(2):124–131

    Article  CAS  PubMed  Google Scholar 

  21. Asnaghi L, Bruno P, Priulla M, Nicolin A (2004) mTOR: a protein kinase switching between life and death. Pharmacol Res 50(6):545–549

    Article  CAS  PubMed  Google Scholar 

  22. Degtyarev M, De Maziere A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183(1):101–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A, Jaattela M (2009) TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28(6):677–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ (2006) AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281(46):34870–34879

    Article  CAS  PubMed  Google Scholar 

  26. Papandreou I, Lim AL, Laderoute K, Denko NC (2008) Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15(10):1572–1581

    Article  CAS  PubMed  Google Scholar 

  27. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590

    Article  CAS  PubMed  Google Scholar 

  28. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Neuzil J, Weber T, Gellert N, Weber C (2001) Selective cancer cell killing by alpha-tocopheryl succinate. Br J Cancer 84(1):87–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu K, Shan YJ, Zhao Y, Yu JW, Liu BH (2001) Inhibitory effects of RRR-alpha-tocopheryl succinate on benzo(a)pyrene (B(a)P)-induced forestomach carcinogenesis in female mice. World J Gastroenterol 7(1):60–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne GC, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey RJ, Weber C (2001) Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. FASEB J 15(2):403–415

    Article  CAS  PubMed  Google Scholar 

  32. Sun Y, Zhao Y, Hou L, Zhang X, Zhang Z, Wu K (2014) RRR-alpha-tocopheryl succinate induces apoptosis in human gastric cancer cells via the NF-kappaB signaling pathway. Oncol Rep 32(3):1243–1248

    CAS  PubMed  Google Scholar 

  33. Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, Korinek V, Sattler W, Ucker DS, Terman A, Schroder A, Erl W, Brunk UT, Coffey RJ, Weber C, Neuzil J (2002) Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clin Cancer Res 8(3):863–869

    CAS  PubMed  Google Scholar 

  34. Hou L, Li Y, Song H, Zhang Z, Sun Y, Zhang X, Wu K (2015) Protective macroautophagy is involved in vitamin e succinate effects on human gastric carcinoma cell line SGC-7901 by inhibiting mTOR axis phosphorylation. PLoS ONE 10(7):e0132829

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T (2001) Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152(4):657–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lin H-Y, Lin J-N, Ma J-W, Yang N-S, Ho C-T, Kuo S-C, Way T-D (2015) Demethoxycurcumin induces autophagic and apoptotic responses on breast cancer cells in photodynamic therapy. J Funct Foods 12:439–449

    Article  CAS  Google Scholar 

  38. Hayashi T, Hirshman MF, Fujii N, Habinowski SA, Witters LA, Goodyear LJ (2000) Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49(4):527–531

    Article  CAS  PubMed  Google Scholar 

  39. Hoyer-Hansen M, Jaattela M (2007) AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 3(4):381–383

    Article  PubMed  Google Scholar 

  40. Alers S, Loffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32(1):2–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, Criollo A, Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio JM, Carnuccio R, Moll UM, Madeo F, Paterlini-Brechot P, Rizzuto R, Szabadkai G, Pierron G, Blomgren K, Tavernarakis N, Codogno P, Cecconi F, Kroemer G (2008) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10(6):676–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Carling D (2004) The AMP-activated protein kinase cascade–a unifying system for energy control. Trends Biochem Sci 29(1):18–24

    Article  CAS  PubMed  Google Scholar 

  43. Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306(5698):990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945

    Article  CAS  PubMed  Google Scholar 

  45. Bonapace L, Bornhauser BC, Schmitz M, Cario G, Ziegler U, Niggli FK, Schafer BW, Schrappe M, Stanulla M, Bourquin JP (2010) Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Investig 120(4):1310–1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102(23):8204–8209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441(7092):437–443

    Article  CAS  PubMed  Google Scholar 

  48. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688

    Article  CAS  PubMed  Google Scholar 

  49. Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18(6):598–608

    Article  CAS  PubMed  Google Scholar 

  50. Berggreen C, Gormand A, Omar B, Degerman E, Goransson O (2009) Protein kinase B activity is required for the effects of insulin on lipid metabolism in adipocytes. Am J physiol Endocrinol Metab 296(4):E635–E646

    Article  CAS  PubMed  Google Scholar 

  51. Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280(37):32081–32089

    Article  CAS  PubMed  Google Scholar 

  52. Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, Schlattner U, Wallimann T, Carling D, Hue L, Rider MH (2006) Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 281(9):5335–5340

    Article  CAS  PubMed  Google Scholar 

  53. Ning J, Xi G, Clemmons DR (2011) Suppression of AMPK activation via S485 phosphorylation by IGF-I during hyperglycemia is mediated by AKT activation in vascular smooth muscle cells. Endocrinology 152(8):3143–3154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by a Grant from the National Natural Science Foundation of China (No. 81172651) to K. Wu.

Author information

Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150086, China

    Yang Yu, Huacui Song, Peixiang Xu, Yue Sun & Kun Wu

  2. School of Public Health, North China University of Science and Technology, Tangshan, China

    Liying Hou

Authors
  1. Yang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liying Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huacui Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peixiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yue Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kun Wu.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, Y., Hou, L., Song, H. et al. Akt/AMPK/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells. Mol Cell Biochem 424, 173–183 (2017). https://doi.org/10.1007/s11010-016-2853-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-016-2853-4

Keywords

Search

Navigation