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Suppression of breast cancer proliferation and induction of apoptosis via AKT and ERK1/2 signal transduction pathways by synthetic polypeptide derived from viral macrophage inflammatory protein II

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Summary

SDF-1α, a ligand for the chemokine receptor CXCR4, is well known for mediating the migration of breast cancer cells. In a previous study we demonstrated that a synthetic 21-mer peptide antagonist of CXCR4 (NT21MP) derived from the viral macrophage inflammatory protein II could antagonize tumor growth in vivo by inhibiting cellular proliferation and inducing apoptosis in breast cancer cells. However, the role of SDF-1α in the signaling pathways underlying the proliferation of human breast cancer cells and associated signaling pathways and inhibiting signal pathways of NT21MP remained unclear. The present study investigated the mechanism of NT21MP on anti-tumor in breast cancer in vitro. The effect of NT21MP on the viability of cells was determined by the MTT assay. Annexin V-FITC and PI staining was performed to detect early stage apoptosis in SKBR3 cells treated with SDF-1α and AMD3100 or NT21MP. Western blotting techniques were used to assay the composition of phosphoproteomics and total proteins present in the SKBR3 breast cancer cells. RT-PCR and Western blotting technique were used to detect the effect of NT21MP and AMD3100 on Bcl-2 and Bax expression. The results indicated that SDF-1α prevented apoptosis and promoted the proliferation of SKBR3 human breast cancer cells. As compared with untreated SKBR3 cells, Treatment with SDF-1α significantly increased cell viability, and NT21MP abolished the protective effects of SDF-1α dose-dependently (P<0.05). There was a significant decrease in the percentage of apoptotic cells after SDF-1α treatment as compared with control group (2.7%±0.2% vs. 5.7%±0.4%, P<0.05). But pretreatment of SKBR3 cells with NT21MP significantly attenuated the antiapoptotic effects of SDF-1α as compared with SKBR3 cells without NT21MP pretreatment. The proliferative and anti-apoptotic effects of SDF-1α in SKBR3 cells were associated with an increase in AKT and ERK1/2 phosphorylation as well as a decrease in Bax expression and an increase in Bcl-2 expression. These changes in intracellular processes were blocked by NT21MP in a dose-dependent manner(P<0.05). In conclusion, NT21MP efficiently inhibits SDF-1α-induced proliferation and antiapoptosis in SKBR3 cells by reducing the levels of phosphorylated AKT and ERK1/2, as well as decreasing the ratio of expression of Bcl-2 relative to Bax.

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References

  1. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity, 2000,12(2): 121–127

    Article  PubMed  CAS  Google Scholar 

  2. Murphy PM, Baggiolini M, Charo IF, et al. International union of pharmacology.XXII. Nomenclature for chemokine receptors. Pharmacol Rev, 2000,52(1):145–176

    PubMed  CAS  Google Scholar 

  3. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer, 2004,4(7):540–550

    Article  PubMed  CAS  Google Scholar 

  4. Zlotnik A. Chemokines and cancer. Int J Cancer, 2006,119(9):2026–2029

    Article  PubMed  CAS  Google Scholar 

  5. Zlotnik A. Involvement of chemokine receptors in organ-specific metastasis. Contrib Microbiol, 2006,13(3): 191–199

    Article  PubMed  CAS  Google Scholar 

  6. Kucia M, Jankowski K, Reca R, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol, 2004,35(3):233–245

    Article  PubMed  CAS  Google Scholar 

  7. Cheng ZJ, Zhao J, Sun Y, et al. beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4. J Biol Chem, 2000,275(4):2479–2485

    Article  PubMed  CAS  Google Scholar 

  8. Lu DY, Tang CH, Yeh WL, et al. SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. Eur J Pharmacol, 2009,613(1–3):146–154

    Article  PubMed  CAS  Google Scholar 

  9. Shen X, Artinyan A, Jackson D, et al. Chemokine receptor CXCR4 enhances proliferation in pancreatic cancer cells through AKT and ERK dependent pathways. Pancreas, 2010,39(1):81–87

    Article  PubMed  CAS  Google Scholar 

  10. Sen P, Mukherjee S, Ray D, et al. Involvement of the Akt/PKB signaling pathway with disease processes. Mol Cell Biochem, 2003,253(1–2):241–246

    Article  PubMed  CAS  Google Scholar 

  11. Kledal TN, Rosenkilde MM, Coulin F, et al. A broad-spectrum chemokine antagonist encoded by Kaposi’s sarcoma-associated herpesvirus. Science, 1997, 277(5332):1656–1659

    Article  PubMed  CAS  Google Scholar 

  12. Zhou NM, Luo ZW, Luo JS, et al. A novel peptide antagonist of CXCR4 derived from the N-terminus of viral chemokine vMIP-II. Biochemistry, 2000,39(13):3782–3787

    Article  PubMed  CAS  Google Scholar 

  13. Mori M, Liu D, Kumar S, et al. NMR structures of anti-HIV D-peptides derived from the N-terminus of viral chemokine vMIP-II. Biochem Biophys Res Commun, 2005,335(3):651–658

    Article  PubMed  CAS  Google Scholar 

  14. Yang QL, Li CH, Ding YX, et al. Inhibitory effect of polypeptide to inhibit CXCR4 on metastasis of breast cancer cell line. CTM, 2008,20(2):89–92

    Google Scholar 

  15. Yang QL, Ding YX, Chen CJ, et al. Suppression of murine breast cancer metastasis by selective inhibition of CXCR4 by synthetic polypeptide derived from viral macrophage inflammatory protein II. Chin Sci Bulletin, 2010,55(20):2152–2159

    Article  CAS  Google Scholar 

  16. Zeng Z, Samudio IJ, Munsell M, et al. Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. Mol Cancer, 2006,5(12):3113–3121

    Article  CAS  Google Scholar 

  17. Lusso P. HIV and the chemokine system: 10 years later. EMBO J, 2006,25(3):447–456

    Article  PubMed  CAS  Google Scholar 

  18. Reeves JD, Piefer AJ. Emerging drug targets for antiretroviral therapy. Drugs, 2005,65(13):1747–1766

    Article  PubMed  CAS  Google Scholar 

  19. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 2006,107(5):1761–1767

    Article  PubMed  CAS  Google Scholar 

  20. Crump MP, Gong JH, Loetscher P, et al. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J, 1997,16(23):6996–7007

    Article  PubMed  CAS  Google Scholar 

  21. Huang X, Shen J, Cui M, et al. Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor. Biophys J, 2003,84(1):171–184

    Article  PubMed  CAS  Google Scholar 

  22. Liang Z, Brooks J, Willard M, et al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun, 2007,359(3):716–722

    Article  PubMed  CAS  Google Scholar 

  23. Wang J, Ying G, Wang J, et al. Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. Cancer Res, 2010,70(2):471–480

    Article  PubMed  CAS  Google Scholar 

  24. Tomita Y, Morooka T, Hoshida Y, et al. Prognostic significance of activated AKT expression in soft-tissue sarcoma. Clin Cancer Res, 2006,12(3):3070–3077

    Article  PubMed  CAS  Google Scholar 

  25. Cinti C, Vindigni C, Zamparelli A, et al. Activated Akt as an indicator of prognosis in gastric cancer. Virchows Arch, 2008,453(5):449–455

    Article  PubMed  CAS  Google Scholar 

  26. Chadha KS, Khoury T, Yu J, et al. Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol, 2006,13(7):933–939

    Article  PubMed  Google Scholar 

  27. Park SS, Kim SW. Activated Akt signaling pathway in invasive ductal carcinoma of the breast: correlation with HER2 overexpression. Oncol Rep, 2007,18(1):139–143

    PubMed  Google Scholar 

  28. Han Z, Hong L, Han Y, et al. Phospho Akt mediates multidrug resistance of gastric cancer cells through regulation of P-gp, Bcl-2 and Bax. J Exp Clin Cancer Res, 2007,26(2):261–268

    PubMed  CAS  Google Scholar 

  29. Bai J, Liu XS, Xu YJ, et al. The effect of ERK signaling pathway on cell apoptosis in airway smooth muscle cells of chronic asthmatic rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (Chinese), 2010,26(8):738–741

    CAS  Google Scholar 

  30. Yang QL, Ding YX, Li CH, et al. Associative research about upregulation of CXCR4 and HER2-mediated breast cancer metastasis. Carcinogen Teratogen Mutagen, 2008,20(4):301–305

    Google Scholar 

  31. Kayaselcuk F, Nursal TZ, Polat A, et al. Expression of survivin, bcl-2, P53 and bax in breast carcinoma and ductal intraepithelial neoplasia (DIN 1a). J Exp Clin Cancer Res, 2004,23(1):105–112

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinical Testing and Diagnosing Experimental Center of Bengbu Medical College, Bengbu, 233030, China

    Qingling Yang  (杨清玲), Changjie Chen  (陈昌杰), Zhifeng Yang  (杨志峰) & Yangjun Gao  (高艳军)

  2. Anhui Key Laboratory of Infection and Immunology, Bengbu, 233000, China

    Jie Tang  (唐 洁)

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  1. Qingling Yang  (杨清玲)
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  2. Changjie Chen  (陈昌杰)
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  3. Zhifeng Yang  (杨志峰)
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  4. Yangjun Gao  (高艳军)
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  5. Jie Tang  (唐 洁)
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Correspondence to Qingling Yang  (杨清玲).

Additional information

The work was supported by a grant from the National Natural Sciences Foundation of China (No. 81071848), as well as a grant from a Key Program of Anhui Educational Committee (No. KJ2010A240).

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Yang, Q., Chen, C., Yang, Z. et al. Suppression of breast cancer proliferation and induction of apoptosis via AKT and ERK1/2 signal transduction pathways by synthetic polypeptide derived from viral macrophage inflammatory protein II. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 31, 497–503 (2011). https://doi.org/10.1007/s11596-011-0479-z

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  • DOI: https://doi.org/10.1007/s11596-011-0479-z

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