Autophagy inhibition through PI3K/Akt increases apoptosis by sodium selenite in NB4 cells

  • Ren, Yun (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Huang, Fang (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Liu, Yuan (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Yang, Yang (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Jiang, Qian (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Xu, Caimin (National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College)
  • Published : 2009.09.30


Selenium possesses the chemotherapeutic feature by inducing apoptosis in cancer cell with trivial side effects on normal cells. However, the mechanism in which is not clearly understood. Emerging evidence indicates the overlaps between the autophagy and the apoptosis. In this study, we have investigated the role of autophagy in selenium-induced apoptosis in NB4 cells. We find that autophagy is suppressed in NB4 cells treated by sodium selenite, as measured by electron microscope, acridine orange staining and western blot. Moreover, selenite combined with autophagy inhibitor contributes to the up-regulation of apoptosis, while the PI3K/Akt signaling pathway is down- regulated. Consistently, when the inhibitor of PI3K was applied, the autophagic level significantly decreased. In summary, sodium selenite increases NB4 cell apoptosis by autophagy inhibition through PI3K/Akt, and the inhibition of autophagy contributes to the up-regulation of apoptosis.


  1. Mizushima, N. (2007) Autophagy: process and function. Genes & Development. 21, 2871-2873
  2. Klionsky, D. J. (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Bio. 8, 931-937
  3. Maiuri, M. C., Zalckvar, E., Kimchi, A. and Kroemer, G. (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Bio. 8, 741-950
  4. Lee, J. A., Gao, F. B. (2008) ESCRT, autophagy, and frontotemporal dementia. BMB Rep. 41, 827-832
  5. Dourmashkin, L. R., Allen, P. D., Gray, A. B., Newland, A. C. and Kelsey, S. M. (1997) Inhibition of autophagy abrogates tumour necrosis factor α induced apoptosis in human T-lymphoblastic leukaemic cells. Br. J. Haematol. 98, 673-685
  6. Klein, E. A. (2004) Selenium: epidemiology and basic science. J. Urol. 171, S50-53
  7. Nelson, M. A., Reid, M., Duffield-Lillico, A. J. and Marshall, J. R. (2002). Prostate cancer and selenium. Urol. Clin. North. Am. 29, 67-70
  8. Rayman, M. P. (2005) Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc. Nutr. Soc. 64, 527-542
  9. Asfour, I. A., Eshazly, S., Fayek, M. H., Hegab, H. M., Raouf, S. and Moussa, M. A. (2006) Effect of high-dose sodium selenite therapy on polymorphonuclear leukocyte apoptosis in non-Hodgkin's lymphoma patients. Biol. Trace. Elem. Res. 110, 19-32
  10. Li, J., Zuo, L., Shen, T., Xu, C. M. and Zhang, Z. N. (2003) Induction of apoptosis by sodium selenite in human acute promyelelocytic leukemia NB4 cells: Involvement of oxidative stress and mitochondria. J. Trace. Elem. Med. Bio. 7, 19-26
  11. Marte, B. M. and Downward, J. (1997) PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem. Sci. 22, 355-358
  12. Kang, H. Y., Shiim, D., Kang, S. S., Chang, S. I. and Kim, H. Y. (2006) Protein kinase B inhibits endostatin-induced apoptosis in HUVECs. J. Biochem. Mol. Biol. 39, 97-104
  13. Han, B., Wei, W., Hua, F., Cao, T., Dong, H., Yang, T., Yang, Y., Pan, H. and Xu, C. (2007) Requirement for ERK activity in sodium selenite-induced apoptosis of acute promyelocytic leukemia-derived NB4 cells. J. Biochem. Mol. Biol. 40, 196-204
  14. Hennessy, B. T., Smith, D. L. and Ram, P. T. (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug. Discov. 4, 988-1004
  15. Zeng, X. and Kinsella, T. J. (2008) Mammalian target of Rapamycin and S6 Kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res. 68, 2384-2390
  16. Guan, L., Han, B., Li, Z., Hua, F., Huang, F., Wei, W., Yang, Y. and Xu, C. (2009) Sodium selenite induces apoptosis by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in human acute promyelocytic leukemia NB4 cells. Apoptosis. 14, 218-225
  17. Bursch, W. (2001) The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 8, 569-581
  18. Seglen, P. O. and Gordon, P. B. (1982) 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 79, 1889-1892
  19. Bowman, E. J., Siebers, A. and Altendorf, K. (1988) Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc. Natl. Acad. Sci. U.S.A 85, 7972-7976
  20. Cui, Q., Tashiro, S., Onodera, S. and Ikejima, T. (2006) Augmentation of oridonin-induced apoptosis observed with reduced autophagy. J. Pharmacol. Sci. 101, 230-239
  21. Klionsky, D. J., Meijer, A. J. and Codogno, P. (2005) Autophagy and p70S6 kinase. Autophagy 1, 59-60
  22. Petiot, A., Ogier-Denis, E., Blommaart, E. F., Meijer, A. J. and Codogno, P. (2000) Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 275, 992-998
  23. Arico, S., Petiot, A., Bauvy, C., Dubbelhuis, P. F., Meijer, A. J., Codogno, P. and Ogier-Denis, E. (2001). The tumorsuppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276, 35243-35246
  24. Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., Mukherjee, C., Shi, Y., Gelinas, C., Fan, Y., Nelson, D. A., Jin, S. and White, E. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51-64
  25. Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A. and Herman, B. (1998). The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta. 1366, 177-196
  26. Amaravadi, R. K., Yu, D., Lum, J. J., Bui, T., Christophorou, M. A., Evan, G. I., Thomas-Tikhonenko, A. and Thompson, C. B. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326-336
  27. Boya, P., Gonzalez-Polo, R. A., Casares, N., Perfettini, J. L., Dessen, P., Larochette, N., Metivier, D., Meley, D., Souquere, S., Yoshimori, T., Pierron, G., Codogno, P. and Kroemer, G. (2004). Inhibition of Macroautophagy Triggers Apoptosis. MCB 25, 1025-1040

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