Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 4, pp 789–798 | Cite as

Inhibition of sorcin reverses multidrug resistance of K562/A02 cells and MCF-7/A02 cells via regulating apoptosis-related proteins

  • Yunhui Hu
  • Xin Cheng
  • Shuangjing Li
  • Yuan Zhou
  • Jianxiang Wang
  • Tao Cheng
  • Ming YangEmail author
  • Dongsheng XiongEmail author
Original Article



Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance (MDR). But the mechanisms mediated by sorcin still remain quite elusive. This study aim to explore whether sorcin silencing could restore chemosensitivity in MDR cancer cells and seek to identify the functional mechanisms mediated by sorcin.


To investigate the mechanisms of sorcin-silencing-induced chemosensitivity, transient expression of sorcin-siRNAs was performed in doxorubicin-induced MDR cell lines, K562/A02 and MCF-7/A02. Sensitivity to five chemotherapeutic agents was evaluated by analysis of cell survival and cell apoptosis.


In this report, we show that down-regulation of sorcin did not alter expression or function of P-gp, but actually induced cell apoptosis and chemosensitivity in K562/A02 and MCF-7/A02. We also observe that silencing of sorcin-enhanced chemotherapeutic agent effects partly through regulating apoptosis-related protein, including Bcl-2, Bax, c-jun and c-fos.


This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer, especially for the reversal of MDR.


Sorcin P-gp Multidrug resistance Apoptosis 



This work was supported by grants from Natural Science Foundation of China (Grant No. 30873091 and 30971291), Natural Science Foundation of Tianjin (Grant No. 05YFGZGX02800) and National Science and Technology Major Project (Grant No. 2009ZX09103-720).


  1. 1.
    Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2(1):48–58PubMedCrossRefGoogle Scholar
  2. 2.
    Steinbach D, Legrand O (2007) ABC transporters and drug resistance in leukemia: was P-gp nothing but the first head of the Hydra? Leukemia 21(6):1172–1176PubMedCrossRefGoogle Scholar
  3. 3.
    Liu F et al (2008) Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line. Life Sci 83(13–14):496–501PubMedCrossRefGoogle Scholar
  4. 4.
    Wang CH et al (2009) Effects of non-cytotoxic drugs on the growth of multidrug-resistance human gastric carcinoma cell line. J Dig Dis 10(2):91–98PubMedCrossRefGoogle Scholar
  5. 5.
    Zhao LJ et al (2012) Modulation of drug resistance in ovarian cancer cells by inhibition of protein kinase C-alpha (PKC-alpha) with small interference RNA (siRNA) agents. Asian Pac J Cancer Prev 13(8):3631–3636PubMedCrossRefGoogle Scholar
  6. 6.
    Ye CG et al (2011) Indomethacin and SC236 enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells via inhibiting P-glycoprotein and MRP1 expression. Cancer Lett 304(2):90–96PubMedCrossRefGoogle Scholar
  7. 7.
    Pu J, Lou F, Zhou Q (1999) In vitro reversal effect of cyclosporin A in combination with cytokines on multidrug resistant cell line K562/A02. Zhonghua Yi Xue Za Zhi 79(3):224–226PubMedGoogle Scholar
  8. 8.
    Meyers MB et al (1995) Association of sorcin with the cardiac ryanodine receptor. J Biol Chem 270(44):26411–26418PubMedCrossRefGoogle Scholar
  9. 9.
    Hamada H et al (1988) Purification of the Mr 22,000 calcium-binding protein (sorcin) associated with multidrug resistance and its detection with monoclonal antibodies. Cancer Res 48(11):3173–3178PubMedGoogle Scholar
  10. 10.
    Roberts D et al (1989) Association of sorcin with drug resistance in L1210 cells. Cancer Chemother Pharmacol 23(1):19–25PubMedCrossRefGoogle Scholar
  11. 11.
    Parekh HK et al (2002) Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells. Biochem Pharmacol 63(6):1149–1158PubMedCrossRefGoogle Scholar
  12. 12.
    He QC, Zhang GY, Cao WJ (2008) Correlation of sorcin overexpression to multidrug resistance of human gastric cancer cell line SGC7901. Ai Zheng 27(4):337–342PubMedGoogle Scholar
  13. 13.
    Qu Y et al (2010) Comparative proteomic profiling identified sorcin being associated with gemcitabine resistance in non-small cell lung cancer. Med Oncol 27(4):1303–1308PubMedCrossRefGoogle Scholar
  14. 14.
    Nagpal JK, Das BR (2007) Identification of differentially expressed genes in tobacco chewing-mediated oral cancer by differential display-polymerase chain reaction. Eur J Clin Invest 37(8):658–664PubMedCrossRefGoogle Scholar
  15. 15.
    Tan Y et al (2003) Expression of sorcin predicts poor outcome in acute myeloid leukemia. Leuk Res 27(2):125–131PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou Y et al (2006) Sorcin, an important gene associated with multidrug-resistance in human leukemia cells. Leuk Res 30(4):469–476PubMedCrossRefGoogle Scholar
  17. 17.
    Yang CZ et al (1995) Multidrug resistance in leukemic cell line K562/A02 induced by doxorubicin. Zhongguo Yao Li Xue Bao 16(4):333–337PubMedGoogle Scholar
  18. 18.
    Shi R et al (2011) A novel indirubin derivative PHII-7 potentiates adriamycin cytotoxicity via inhibiting P-glycoprotein expression in human breast cancer MCF-7/ADR cells. Eur J Pharmacol 669(1–3):38–44PubMedCrossRefGoogle Scholar
  19. 19.
    Batist G et al (1986) Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J Biol Chem 261(33):15544–15549PubMedGoogle Scholar
  20. 20.
    Qi J et al (2002) Function and mechanism of pyronaridine: a new inhibitor of P-glycoprotein-mediated multidrug resistance. Acta Pharmacol Sin 23(6):544–550PubMedGoogle Scholar
  21. 21.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63PubMedCrossRefGoogle Scholar
  22. 22.
    Yague E et al (2003) P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation. J Biol Chem 278(12):10344–10352PubMedCrossRefGoogle Scholar
  23. 23.
    Hwang M, Moretti L, Lu B (2009) HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy. Curr Med Chem 16(24):3081–3092PubMedCrossRefGoogle Scholar
  24. 24.
    Kellner U et al (1997) Decreased drug accumulation in a mitoxantrone-resistant gastric carcinoma cell line in the absence of P-glycoprotein. Int J Cancer 71(5):817–824PubMedCrossRefGoogle Scholar
  25. 25.
    Beyer-Sehlmeyer G et al (1999) Suppressive subtractive hybridisation reveals differential expression of serglycin, sorcin, bone marrow proteoglycan and prostate-tumour-inducing gene I (PTI-1) in drug-resistant and sensitive tumour cell lines of haematopoetic origin. Eur J Cancer 35(12):1735–1742PubMedCrossRefGoogle Scholar
  26. 26.
    Kawakami M et al (2007) Knock-down of sorcin induces up-regulation of MDR1 in HeLa cells. Biol Pharm Bull 30(6):1065–1073PubMedCrossRefGoogle Scholar
  27. 27.
    Wang SL et al (1995) Isolation and molecular cloning of human sorcin a calcium-binding protein in vincristine-resistant HOB1 lymphoma cells. Biochim Biophys Acta 1260(3):285–293PubMedCrossRefGoogle Scholar
  28. 28.
    Lee WP (1996) Purification, cDNA cloning, and expression of human sorcin in vincristine-resistant HOB1 lymphoma cell lines. Arch Biochem Biophys 325(2):217–226PubMedCrossRefGoogle Scholar
  29. 29.
    Landriscina M et al (2010) Mitochondrial chaperone Trap1 and the calcium binding protein sorcin interact and protect cells against apoptosis induced by antiblastic agents. Cancer Res 70(16):6577–6586PubMedCrossRefGoogle Scholar
  30. 30.
    Mikula M et al (2003) The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis. Oncogene 22(43):6725–6738PubMedCrossRefGoogle Scholar
  31. 31.
    Herrlich P (2001) Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20(19):2465–2475PubMedCrossRefGoogle Scholar
  32. 32.
    Deng L et al (2010) Upregulation of soluble resistance-related calcium-binding protein (sorcin) in gastric cancer. Med Oncol 27(4):1102–1108PubMedCrossRefGoogle Scholar
  33. 33.
    Maddalena F et al (2013) Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Mol Oncol. pii: S1574-7891(13)00079-3Google Scholar
  34. 34.
    Diaz-Blanco E et al (2007) Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 21(3):494–504PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yunhui Hu
    • 1
    • 2
  • Xin Cheng
    • 1
    • 3
  • Shuangjing Li
    • 1
  • Yuan Zhou
    • 1
  • Jianxiang Wang
    • 1
  • Tao Cheng
    • 1
  • Ming Yang
    • 1
    Email author
  • Dongsheng Xiong
    • 1
    Email author
  1. 1.State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology and Hospital of Blood DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinPeople’s Republic of China
  2. 2.National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of EducationTianjin Medical University Institute and HospitalTianjinPeople’s Republic of China
  3. 3.Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of ZoologyChinese Academy of SciencesBeijingPeople’s Republic of China

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