Tumor Biology

, Volume 35, Issue 6, pp 5381–5388 | Cite as

Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy

  • Hui-Wen Yan
  • Wei-Xin Hu
  • Jie-Ying Zhang
  • Ye Wang
  • Kun Xia
  • Min-Yuan Peng
  • Jing Liu
Research Article


Resveratrol (Res) is a naturally occurring phytoalexin with apoptotic and inducing-glob effects in leukemic cells, but the potential induction of erythroid differentiation in cells is not fully understood. Here, we investigated the effects of Res on human erythro-megakaryoblastic leukemia cell line K562. Among the treated cells, proliferation was inhibited and the occurrence of cell apoptosis and cell death were detected. Erythroid differentiation assay was explored, and we found that Res could increase the expression of glycophorin A (GPA), HBA1, HBB, and γ-globin genes and enforced the expression of GPA, CD71, and Band3 proteins. Res also induced K562 cell autophagy when the concentration of Res was increased up to 50 or 100 μM. Our findings suggested that Res possesses the potency not only inducing apoptosis but also inducing erythroid differentiation and autophagy in K562 cells. These results provide that Res may be a therapeutic candidate for chronic myelogenous leukemia treatment.


Resveratrol K562 cells Apoptosis Erythroid differentiation Autophagy 



The authors thank the financial support from the National Natural Science Foundation of China (grant nos.81270576 and 81372538), New Century Excellent Talents in University (NCET-11-0518), Doctoral fund of the Ministry of Education of China (no. 20120162110054), the Fundamental Research Funds for the Central Universities (no. 2011JQ015), Open Project of Xinjiang Key Laboratory of Biological Resources and Genetic Engineering (XJDX0201_2012_07 and XJDX_0201_2012_09), and the Innovation Experiment Program for Graduate Students of the Central South University (nos. YB13027, CY12363, and CY12364).

Conflicts of interest



  1. 1.
    Clarkson B, Strife A. Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment. Leukemia. 1993;7:1683–721.PubMedGoogle Scholar
  2. 2.
    Lazzio CB, Lazzio BB. Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood. 1975;45:321–34.Google Scholar
  3. 3.
    Klein E, Ben-Bassat H, Neumann H, Ralph P, Zeuthen J, Polliack A, et al. Properties of the K562 cell line, derived from a patient with chronic myeloid leukemia. Int J Cancer. 1976;18:421–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Melo JV. The molecular biology of chronic myeloid leukaemia. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 1996;10:751–6.Google Scholar
  5. 5.
    Advani AS, Pendergast AM. Bcr-Abl variants: biological and clinical aspects. Leuk Res. 2002;26:713–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Bruecher-Encke B, Griffin JD, Neel BG, Lorenz U. Role of the tyrosine phosphtase SHP-1 in K562 cell differentiation. Leukemia. 2001;15:1424–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Tabilio A, Pelicci P, Vinci G, Mannoni P, Civin CI, Vainchenker W, et al. Myeloid and megakaryocytic properties of K-562 cell lines. Cancer Res. 1983;43:4569–74.PubMedGoogle Scholar
  8. 8.
    Meshkini A, Yazdanparast R. Induction of megakaryocytic differentiation in chronic myelogenous leukemia cell K562 by 3-hydrogenkwadaphnin. Biochem Mol Biol. 2007;40:944–51.CrossRefGoogle Scholar
  9. 9.
    Alitalo R. Induced differentiation of K562 leukemia cells: a model for studies of gene expression in early megakaryoblasts. Leuk Res. 1990;14:501–14.CrossRefPubMedGoogle Scholar
  10. 10.
    Sutherland JA, Turner AR, Mannoni P, McGann LE, Turc JM. Differentiation of K562 leukemia cell along eryhroid, macrophage, and megakaryocyte lineage. J Biol Respir Mod. 1986;5:25–62.Google Scholar
  11. 11.
    Huang HL, Chen YC, Huang YC, Yang KC, Pan H, Shih SP, et al. Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells. PLoS One. 2011;6:e29014.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    D'Introno A, Paradiso A, Scoditti E, D'Amico L, De Paolis A, Carluccio MA, et al. Antioxidant and anti-inflammatory properties of tomato fruits synthesizing different amounts of stilbenes. Plant Biotechnol J. 2009;7:422–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Schubert R, Fischer R, Hain R, Schreier PH, Bahnweg G, Ernst D, et al. An ozoneresponsive region of the grapevine resveratrol synthase promoter differs from the basal pathogen-responsive sequence. Plant Mol Biol. 1997;34(3):417–26.CrossRefPubMedGoogle Scholar
  14. 14.
    Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem. 1997;30:91–113.CrossRefPubMedGoogle Scholar
  15. 15.
    Hsieh TC, Wang Z, Hamby CV, Wu JM. Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53. Biochem Biophys Res Commun. 2005;334:223–30.CrossRefPubMedGoogle Scholar
  16. 16.
    Wu CP, Calcagno AM, Hladky SB, Ambudkar SV, Barrand MA. Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J. 2005;272:4725–40.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Damianaki A, Bakogeorgou E, Kampa M, Notas G, Hatzoglou A, Panagiotou S, et al. Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem. 2000;78:429–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Gautam SC, Xu YX, Dumaguin M, Janakiraman N, Chapman RA. Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging. Bone Marrow Transplant. 2000;25:639–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999;59:5892–5.PubMedGoogle Scholar
  20. 20.
    Pozo-Guisado E, Alvarez-Barrientos A, Mulero-Navarro S, Santiago-Josefat B, Fernandez-Salguero PM. The anti- proliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alteration of the cell cycle. Biochem Pharmacol. 2012;13:1375–86.Google Scholar
  21. 21.
    Schneider Y, Vincent F, Duranton B, Badolo L, Gosse F, Raul F. Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett. 2000;158:85–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhou HB, Yan Y, Sun YN, Zhu JR. Resveratrol induces apoptosis in human esophageal carcinoma cells. World J Gastroenterol. 2003;9:408–11.PubMedGoogle Scholar
  23. 23.
    Wang Z, Zou J, Cao K, Hsieh TC, Huang Y, Wu JM. Dealcoholized red wine containing known amounts of resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits without affecting plasma lipid levels. Int J Mol Med. 2005;16:533–40.PubMedGoogle Scholar
  24. 24.
    Wu JM, Wang ZR, Hsieh TC, Bruder JL, Zou JG, Huang YZ. Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine. Int J Mol Med. 2001;8:3–17.PubMedGoogle Scholar
  25. 25.
    Rossi D, Guerrini A, Bruni R, Brognara E, Borgatti M, Gambari R, et al. Trans-resveratrol in nutraceuticals: issues in retail quality and effectiveness. Molecules. 2012;17:12393–405.CrossRefPubMedGoogle Scholar
  26. 26.
    Luzi C, Brisdelli F, Cinque B, Cifone G, Bozzi A. Differential sensitivity to resveratrol-induced apoptosis of human chronic myeloid (K562) and acute lymphoblastic (HSB-2) leukemia cells. Biochem Pharmacol. 2004;68:2019–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Chakraborty PK, Mustafi SB, Ganguly S, Chatterjee M, Raha S. Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) cells by targeting a key survival protein, heat shock protein 70. Cancer Sci. 2008;99:1109–16.CrossRefPubMedGoogle Scholar
  28. 28.
    Puissant A, Grosso S, Jacquel A, Belhacene N, Colosetti P, Cassuto JP, et al. Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol. FASEB J. 2008;22:1894–904.CrossRefPubMedGoogle Scholar
  29. 29.
    Santos Franco S, De Falco L, Ghaffari S, Brugnara C, Sinclair DA, Mattè A, Iolascon A, Mohandas N, Bertoldi M, An X, Siciliano A, Rimmelé P, Cappellini MD, Michan S, Zoratti E, Janin A, De Franceschi L. Resveratrol accelerates erythroid maturation by activation of FOXO3 and ameliorates anemia in beta-thalassemic mice. Haematologica 2014; (in press)Google Scholar
  30. 30.
    Fibach E, Prus E, Bianchi N, Zuccato C, Breveglieri G, Salvatori F, et al. Resveratrol: antioxidant activity and induction of fetal hemoglobin in erythroid cells from normal donors and β-thalassemia patients. Int J Mol Med. 2012;29:974–82.PubMedGoogle Scholar
  31. 31.
    Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A. 2009;106:17413–8.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Liu J, Narla M, An X. Membrane assembly during erythropoiesis. Curr Opin Hematol. 2011;18:133–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Hu J, Liu J, Xue F, Halverson G, Reid M, Guo A, et al. Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo. Blood. 2013;121(16):3246–53.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(/)5b(/) mice due to decreased survival of early erythroblasts. Blood. 2001;98(12):3261–73.CrossRefPubMedGoogle Scholar
  35. 35.
    Asou H, Koshizuka K, Kyo T, Takata N, Kamada N, Koeffier HP. Resveratrol, a natural product derived from grapes, is a new inducer of differentiation in human myeloid leukemias. Int J Hematol. 2002;75:528–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Cao Y, Wang F, Liu HY, Fu ZD, Han R. Resveratrol induces apoptosis and differentiation in acute promyelocytic leukemia (NB4) cells. J Asian Nat Prod Res. 2005;7:633–41.CrossRefPubMedGoogle Scholar
  37. 37.
    Rodrigue CM, Arous N, Bachir D, Smith-Ravin J, Romeo PH, Galacteros F, et al. Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea towards erythroid differentiation. Br J Haematol. 2001;113:500–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 2010;70:1042–52.CrossRefPubMedGoogle Scholar
  40. 40.
    Griffiths RE, Kupzig S, Cogan N, Mankelow TJ, Betin VM, Trakarnsanga K, et al. The ins and outs of human reticulocyte maturation: autophagy and the endosome/exosome pathway. Autophagy. 2012;8:1150–1.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Hui-Wen Yan
    • 1
    • 3
  • Wei-Xin Hu
    • 1
  • Jie-Ying Zhang
    • 1
  • Ye Wang
    • 1
  • Kun Xia
    • 2
  • Min-Yuan Peng
    • 4
  • Jing Liu
    • 1
  1. 1.Molecular Biology Research Center, School of Life ScienceCentral South UniversityChangshaChina
  2. 2.State Key Laboratory of Medical Genetics of ChinaCentral South UniversityChangshaChina
  3. 3.Department of Cell Biology, School of Life ScienceCentral South UniversityChangshaChina
  4. 4.Department of HematologyXiangya Hospital, Central South UniversityChangshaChina

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