Journal of Cancer Prevention

Korean Society of Cancer Prevention (대한암예방학회)
권호 표지

Quercetin Regulates Sestrin 2-AMPK-mTOR Signaling Pathway and Induces Apoptosis via Increased Intracellular ROS in HCT116 Colon Cancer Cells

  • Kim, Guen Tae (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University) ;
  • Lee, Se Hee (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University) ;
  • Kim, Young Min (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University)
  • Published : 2013.09.30
⟨ Previous Next ⟩

Abstract

Background: The suppression of abnormal cell proliferation is therapeutic strategies for the treatment of cancer. In this study, we investigated the regulatory mechanism of quercetin-induced apoptosis through regulation of Sestrin 2 and AMPK signaling pathway. Methods: After treatment of quercetin to colon cancer cells, intracellular ROS was detected using by DCFH-DA. To examine how quercetin and $H_2O_2$ induced apoptosis, we analyzed the change of Sestrin 2, p53 expression and p-AMPK$\alpha$1, p-mTOR levels by Western blotting. To evaluate the effect of intracellular ROS generated by quercetin on colon cancer cells, NAC, anti-oxidative agent, was co-treated. Results: Quercetin increased apoptotic cell death though generating intracellular reactive oxygen species (ROS), and it was responsible for Sestrin 2 expression. Increased Sestrin 2 expression was accompanied by AMPK activation. Interestingly, mTOR activity by Sestirn 2 expression was dependent on AMPK phosphorylation. On the other hand, the expression of Sestrin 2 by quercetin-generated intracellular ROS was independent of p53. Conclusions: We suggested that quercetin-induced apoptosis involved Sestrin 2/AMPK/mTOR pathway, which was regulated by increased intracellular ROS by quercetin.

Keywords

References

  1. Jung KW, Park S, Kong HJ, Won YJ, Lee JY, Seo HG, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. Cancer Res Treat 2012;44:11-24. https://doi.org/10.4143/crt.2012.44.1.11
  2. Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E, et al. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med 2011;2011:591356.
  3. Chien SY, Wu YC, Chung JG, Yang JS, Lu HF, Tsou MF, et al. Quercetin-induced apoptosis acts through mitochondrial- and capase-2-dependent pathways in human breast cancer MDA-MB-231 cells. Hum Exp Toxicol 2009;28:493-503. https://doi.org/10.1177/0960327109107002
  4. Lee YK, Hwang JT, Kwon DY, Surh YJ, Park OJ. Induction of apoptosis by quercetin is mediated through AMPKalpha1/ ASK1/p38 pathway. Cancer Lett 2010;292:228-36. https://doi.org/10.1016/j.canlet.2009.12.005
  5. Tanigawa S, Fujii M, Hou DX. Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci Biotechnol Biochem 2008;72:797-804. https://doi.org/10.1271/bbb.70680
  6. Amol J. Levine, p53, the cellular gatekeeper for growth and division. Cell 1997;88:323-31. https://doi.org/10.1016/S0092-8674(00)81871-1
  7. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. PNAS 2005;102:8204-9. https://doi.org/10.1073/pnas.0502857102
  8. Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 2002;21:6017-31. https://doi.org/10.1038/sj.onc.1205877
  9. Alexander A, Walker CL. The p53-regulated Sestrin gene product inhibit mTOR signaling. Cell 2008;134:451-60. https://doi.org/10.1016/j.cell.2008.06.028
  10. Sanli T, Linher-Melville K, Tsakiridis T, Singh G. Sestrin2 modulates AMPK subunit expression and Its response to Ionizing Radiation in breast cancer cells. PLoS One 2012;7:e32035. https://doi.org/10.1371/journal.pone.0032035
  11. Budanov AV, Karin M. The role of LKB1 and AMPK in cellular responses to stress and damage. FEBS Lett 2011;585:952-7. https://doi.org/10.1016/j.febslet.2011.03.010
  12. 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
  13. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/ Akt/mTOR pathway-Beyond rapalogs. Oncotarget 2010;1:530-43.
  14. Mouria M, Gukovskaya AS, Jung Y, Buechler P, Hines OJ, Reber HA, et al. Food-derived polyphenols inhibit pancreatic cancer growth through mitochondria cytochrome C release and apoptosis. Int J Cancer 2002;98:761-9. https://doi.org/10.1002/ijc.10202
  15. Lee YK, Park SY, Kim YM, Lee WS, Park OJ. AMP kinase/ cyclooxygenase-2 pathway regulates proliferation and apoptosis of cancer cells treated with quercetin. Exp Mol Med 2009;41:201-7. https://doi.org/10.3858/emm.2009.41.3.023
  16. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2:a001008.