Skip to main content

Advertisement

SpringerLink
Log in

Creation of an apoptin-derived peptide that interacts with SH3 domains and inhibits glioma cell migration and invasion

  • Original Article
  • Published:
Tumor Biology

Abstract

Glioblastoma multiforme (GBM) is an aggressive tumor of the central nervous system characterized by high rates of recurrence, morbidity, and mortality. This study investigated the antitumor effects of an apoptin-derived peptide (ADP) on glioma cells and explored the underlying mechanisms. The U251, U87, and C6 glioma cell lines were used in the present study, and the expression of p-Akt, Akt, and MMP-9 was determined through Western blotting, quantitative real-time PCR, and hematoxylin and eosin (HE) staining. Tumor growth was evaluated by magnetic resonance imaging, and cell viability was assessed through an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT assay. Glioma cell metastasis was evaluated using transwell migration, invasion, and scratch-wound assays. An ADP was designed and synthesized based on the results of a domain-based analysis of the structure of apoptin. The ADP inhibited glioma cell viability, invasion and migration, and treatment with the synthesized ADP led to downregulation of p-Akt and MMP-9 and inhibited MMP-9 translation. The ADP also inhibited glioma invasion and migration in vivo, and HE staining showed decreases in the satellite-like invasion of cell masses and apoptotic cell populations after treatment with the ADP. Our findings demonstrate that treatment with an ADP can suppress glioma cell migration and invasion via the PI3K/Akt/MMP-9 signaling pathway and provide a new platform for the development of drugs for treating glioma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. doi:10.1056/NEJMoa043330.

    Article  CAS  PubMed  Google Scholar 

  2. Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot JF, Mills GB, Yung WK. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther. 2006;5:637–44. doi:10.1158/1535-7163.MCT-05-0453.

    Article  CAS  PubMed  Google Scholar 

  3. Griscelli F, Li H, Cheong C, Opolon P, Bennaceur-Griscelli A, Vassal G, Soria J, Soria C, Lu H, Perricaudet M, Yeh P. Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model. Proc Natl Acad Sci U S A. 2000;97:6698–703. doi:10.1073/pnas.110134297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Backendorf C, Visser AE, de Boer AG, Zimmerman R, Visser M, Voskamp P, Zhang YH, Noteborn M. Apoptin: therapeutic potential of an early sensor of carcinogenic transformation. Annu Rev Pharmacol Toxicol. 2008;48:143–69. doi:10.1146/annurev.pharmtox.48.121806.154910.

    Article  CAS  PubMed  Google Scholar 

  5. Kita D, Yonekawa Y, Weller M, Ohgaki H. PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 2007;113:295–302. doi:10.1007/s00401-006-0186-1.

    Article  CAS  PubMed  Google Scholar 

  6. Cámara-Artigas A, Martín-García JM, Morel B, Ruiz-Sanz J, Luque I. Intertwined dimeric structure for the SH3 domain of the c-Src tyrosine kinase induced by polyethylene glycol binding. FEBS Lett. 2009;583:749–53. doi:10.1016/j.febslet.2009.01.036.

    Article  PubMed  Google Scholar 

  7. Noteborn MH, Koch G. Chicken anaemia virus infection: molecular basis of pathogenicity. Avian Pathol. 1995;24:11–31. doi:10.1080/03079459508419046.

    Article  CAS  PubMed  Google Scholar 

  8. Singh PK, Tiwari AK, Rajmani RS, Kumar GR, Chaturvedi U, Saxena L, Saxena S, Doley J, Sahoo AP, Santra L, Saxena M, Kumar S, Sharma B. Apoptin as a potential viral gene oncotherapeutic agent. Appl Biochem Biotechnol. 2015;176:196–212. doi:10.1007/s12010-015-1567-5.

    Article  CAS  PubMed  Google Scholar 

  9. Danen-Van Oorschot AAAM, Zhang YH, Leliveld SR, Rohn JL, Seelen MC, Bolk MW, Van Zon A, Erkeland SJ, Abrahams JP, Mumberg D, Noteborn MH. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis. J Biol Chem. 2003;278:27729–36.

    Article  CAS  PubMed  Google Scholar 

  10. Rollano Peñaloza OM, Lewandowska M, Stetefeld J, Ossysek K, Madej M, Bereta J, Sobczak M, Shojaei S, Ghavami S, Łos MJ. Apoptins: selective anticancer agents. Trends Mol Med. 2014;20:519–28. doi:10.1016/j.molmed.2014.07.003.

    Article  PubMed  Google Scholar 

  11. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 2004;116:527–40. doi:10.1016/S0092-8674(04)00162-X.

    Article  CAS  PubMed  Google Scholar 

  12. Burek M, Maddika S, Burek CJ, Daniel PT, Schulze-Osthoff K, Los M. Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1 dependent. Oncogene. 2006;25:2213–22. doi:10.1038/sj.onc.1209258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yuan L, Zhao H, Zhang L, Liu X. The efficacy of combination therapy using adeno-associated virus-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma. Tumour Biol. 2013;34:3027–34. doi:10.1007/s13277-013-0867-z.

    Article  CAS  PubMed  Google Scholar 

  14. Yang X, Wang J, Zhou Y, Wang Y, Wang S, Zhang W. Hsp70 promotes chemoresistance by blocking Bax mitochondrial translocation in ovarian cancer cells. Cancer Lett. 2012;321:137–43. doi:10.1016/j.canlet.2012.01.030.

    Article  CAS  PubMed  Google Scholar 

  15. Yuan L, Zhang L, Dong X, Zhao H, Li S, Han D, Liu X. Apoptin selectively induces the apoptosis of tumor cells by suppressing the transcription of HSP70. Tumour Biol. 2013;34:577–85. doi:10.1007/s13277-012-0585-y.

    Article  CAS  PubMed  Google Scholar 

  16. Poon IK, Oro C, Dias MM, Zhang J, Jans DA. Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells. Cancer Res. 2005;65:7059–64. doi:10.1158/0008-5472.CAN-05-1370.

    Article  CAS  PubMed  Google Scholar 

  17. Danen V, Oorschot AA, Zhang YH, Leliveld SR, Jennifer LR, Maud CMJS, Marian WB, Van Zon A, Stefan JE, Jan PA, Dominik M, Mathieu HMN. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis. J Biol Chem. 2003;13:27729–36.

    Article  Google Scholar 

  18. Los M, Panigrahi S, Rashedi I, Mandal S, Stetefeld J, Essmann F, Schulze-Osthoff K. Apoptin, a tumor-selective killer. Biochim Biophys Acta. 2009;1793:1335–42. doi:10.1016/j.bbamcr.2009.04.002.

    Article  CAS  PubMed  Google Scholar 

  19. Rohn JL, Zhang YH, Aalbers RI, Otto N, Den Hertog J, Henriquez NV, van de Velde CJ, Kuppen PJ, Mumberg D, Donner P, Noteborn MH. A tumor-specific kinase activity regulates the viral death protein apoptin. J Biol Chem. 2002;277:50820–7. doi:10.1074/jbc.M208557200.

    Article  CAS  PubMed  Google Scholar 

  20. Lee YH, Cheng CM, Chang YF, Wang TY, Yuo CY. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity. Biochem Biophys Res Commun. 2007;354:391–5. doi:10.1016/j.bbrc.2006.12.201.

    Article  CAS  PubMed  Google Scholar 

  21. Leliveld SR, Dame RT, Mommaas MA, Koerten HK, Wyman C, Danen-van Oorschot AA, Rohn JL, Noteborn MH, Abrahams JP. Apoptin protein multimers form distinct higher-order nucleoprotein complexes with DNA. Nucleic Acids Res. 2003;31:4805–13. doi:10.1093/nar/gkg661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heilman DW, Teodoro JG, Green MR. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies. J Virol. 2006;80:7535–45. doi:10.1128/JVI.02741-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rohn JL, Zhang YH, Aalbers RI, Otto N, Den Hertog J, Henriquez NV, van de Velde CJ, Kuppen PJ, Mumberg D, Donner P, Noteborn MH. A tumor-specific kinase activity regulates the viral death protein apoptin. J Biol Chem. 2002;277:50820–7. doi:10.1074/jbc.M208557200.

    Article  CAS  PubMed  Google Scholar 

  24. Ma C, Li Y, Zhang X, Zhao G, Xu H. Levels of vascular endothelial growthfactor and matrix metalloproteinase-9 proteins in patients with glioma. J Int Med Res. 2014;42:198–204. doi:10.1177/0300060513481924.

    Article  CAS  PubMed  Google Scholar 

  25. Fan F, Schimming A, Jaeger D, Podar K. Targeting the tumor microenvironment: focus on angiogenesis. J Oncol. 2012;2012:281261. doi:10.1155/2012/281261.

    Article  PubMed  Google Scholar 

  26. Choe G, Park JK, Jouben-Steele L, Kremen TJ, Liau LM, Vinters HV, Cloughesy TF, Mischel PS. Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype. Clin Cancer Res. 2002;8:2894–901.

    CAS  PubMed  Google Scholar 

  27. Awasthi R, Pandey CM, Sahoo P, Behari S, Kumar V, Kumar S, Misra S, Husain N, Soni P, Rathore RK, Gupta RK. Dynamic contrast-enhanced magnetic resonance imaging-derived kep as a potential biomarker of matrix metalloproteinase 9 expression in patients with glioblastoma multiforme: a pilot study. J Comput Assist Tomogr. 2012;36:125–30. doi:10.1097/RCT.0b013e31823f6c59.

    Article  PubMed  Google Scholar 

  28. Zhao Y, Lyons Jr CE, Xiao A, Templeton DJ, Sang QA, Brew K, Hussaini IM. Urokinase directly activates matrix metalloproteinases-9: a potential role in glioblastoma invasion. Biochem Biophys Res Commun. 2008;369:1215–20. doi:10.1016/j.bbrc.2008.03.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81502676) and the Heilongjiang Province Postdoctoral Science Foundation (Grant No. LBH-Z14157), awarded to Dr. Wu Liande as well as by an e-Fund (WLD-QN110).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Harbin Medical University, Harbin, People’s Republic of China

    Weiwei Song & Lijie Yuan

  2. Daqing Oilfield General Hospital, Daqing, People’s Republic of China

    Hengyu Zhao

  3. Department of Biochemistry and Molecular Biology, Daqing Campus, Harbin Medical University, Daqing, Heilongjiang, 163319, People’s Republic of China

    Zhongqi Cui, Xiaoyu Ma, Wenwen Zhang, Di Wang, Anqi Liu & Lijie Yuan

Authors
  1. Weiwei Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hengyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhongqi Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoyu Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Di Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anqi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lijie Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lijie Yuan.

Ethics declarations

The use of animals was approved by the ethics committees of Harbin Medical University, and all experimental procedures were conducted in accordance with the regulations of the ethics committees of Harbin Medical University. All experimental and animal care procedures followed protocols that were approved by the local institutional review board and ethics committee according to national regulations.

Conflict of interest

None.

Additional information

Weiwei Song and Hengyu Zhao contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, W., Zhao, H., Cui, Z. et al. Creation of an apoptin-derived peptide that interacts with SH3 domains and inhibits glioma cell migration and invasion. Tumor Biol. 37, 15229–15240 (2016). https://doi.org/10.1007/s13277-016-5404-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5404-4

Keywords

Search

Navigation