Cytotechnology

, Volume 70, Issue 1, pp 153–161 | Cite as

Glioma targeting peptide in combination with the P53 C terminus inhibits glioma cell proliferation in vitro

Original Article

Abstract

Glioma is a prevalent malignant primary brain tumor in adults, the treatment for which remains a challenge due to its high infiltration and recurrence. Hence, treatments that lead to the suppression of glioma cell migration and invasion may be used in addition to surgery to increase the therapeutic outcome. In this study, we aimed to construct a multifunctional protein that would exert an effect on glioma cell proliferation and migration. The protein is named GL1-P53C-11R and it consists of the glioma-targeting peptide GL1 (G), the P53 C terminus (Pc) and the cell-penetrating peptide arginine (R). GL1-P53C-R was expressed with the fusion protein ZZ and immunofluorescence analysis showed effective delivery of the fused ZZ-GL1-P53C-R protein represented as ZZ-GPcR. The ZZ-GPcR exhibited an inhibitory effect on the proliferation, migration and invasion of U87ΔEGFR cells. Western blotting results indicated that it caused significant changes in the expression levels of cell cycle and apoptotic proteins. Flow cytometric analysis showed increase apoptosis. Our findings suggest that the P53C in the fusion protein ZZ-GPcR can enter into glioma cells to exert its inhibitory effect.

Keywords

Glioma Targeting peptide P53 C terminus Cell proliferation Apoptosis 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81371676, 81071248) and the fundamental research fund of the key laboratory of Liaoning Provincial Education Department (LZ2015049).

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interests.

References

  1. Appin CL, Gao J, Chisolm C, Torian M, Alexis D, Vincentelli C, Schniederjan MJ, Hadjipanayis C, Olson JJ, Hunter S, Hao C, Brat DJ (2013) Glioblastoma with oligodendroglioma component (GBM-O): molecular genetic and clinical characteristics. Brain Pathol 23:454–461CrossRefGoogle Scholar
  2. Araki D, Takayama K, Inoue M, Watanabe T, Kumon H, Futaki S, Matsui H, Tomizawa K (2010) Cell-penetrating D-isomer peptides of p53 C-terminus: long-term inhibitory effect on the growth of bladder cancer. Urology 75:813–819CrossRefGoogle Scholar
  3. Bolhassani A, Jafarzade BS, Mardani G (2017) In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides. Peptides 87:50–63CrossRefGoogle Scholar
  4. Chen S, Rong L, Lei Q, Cao PX, Qin SY, Zheng DW, Jia HZ, Zhu JY, Cheng SX, Zhuo RX, Zhang XZ (2016) A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy. Biomaterials 77:149–163CrossRefGoogle Scholar
  5. Cho JH, Kim AR, Kim SH, Lee SJ, Chung H, Yoon MY (2017) Development of a novel imaging agent using peptide-coated gold nanoparticles toward brain glioma stem cell marker CD133. Acta Biomater 47:182–192CrossRefGoogle Scholar
  6. Chugh A, Eudes F, Shim YS (2010) Cell-penetrating peptides: nanocarrier for macromolecule delivery in living cells. IUBMB Life 62:183–193CrossRefGoogle Scholar
  7. Clark PM, Mai WX, Cloughesy TF, Nathanson DA (2016) Emerging approaches for targeting metabolic vulnerabilities in malignant glioma. Curr Neurol Neurosci Rep 16:17CrossRefGoogle Scholar
  8. Dinca A, Chien WM, Chin MT (2016) Intracellular delivery of proteins with cell-penetrating peptides for therapeutic uses in human disease. Int J Mol Sci 17:263CrossRefGoogle Scholar
  9. Emdad L, Dent P, Sarkar D, Fisher PB (2012) Future approaches for the therapy of malignant glioma: targeting genes mediating invasion. Future Oncol 8:343–346CrossRefGoogle Scholar
  10. Feng B, Zhao CH, Tanaka S, Imanaka H, Imamura K, Nakanishi K (2007) TPR domain of Ser/Thr phosphatase of Aspergillus oryzae shows no auto-inhibitory effect on the dephosphorylation activity. Int J Biol Macromol 41:281–285CrossRefGoogle Scholar
  11. Fischer I, Aldape K (2010) Molecular tools: biology, prognosis, and therapeutic triage. Neuroimaging Clin N Am 20:273–282CrossRefGoogle Scholar
  12. Fonseca SB, Pereira MP, Kelley SO (2009) Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv Drug Deliv Rev 61:953–964CrossRefGoogle Scholar
  13. Gan HK, Kaye AH, Luwor RB (2009) The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 16:748–754CrossRefGoogle Scholar
  14. Hamard PJ, Lukin DJ, Manfredi JJ (2012) p53 basic C terminus regulates p53 functions through DNA binding modulation of subset of target genes. J Biol Chem 287:22397–22407CrossRefGoogle Scholar
  15. Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol 157:195–206CrossRefGoogle Scholar
  16. Ho IA, Hui KM, Lam PY (2010) Isolation of peptide ligands that interact specifically with human glioma cells. Peptides 31:644–650CrossRefGoogle Scholar
  17. Kamei N, Bech Nielsen EJ, Nakakubo T, Aoyama Y, Rahbek UL, Pedersen BL, Takeda-Morishita M (2016) Applicability and limitations of cell-penetrating peptides in non-covalent mucosal drug or carrier delivery systems. J Pharm Sci 105:747–753CrossRefGoogle Scholar
  18. Krautwald S, Dewitz C, Fändrich F, Kunzendorf U (2016) Inhibition of regulated cell death by cell-penetrating peptides. Cell Mol Life Sci 73:2269–2284CrossRefGoogle Scholar
  19. Laptenko O, Tong DR, Manfredi J, Prives C (2016) The tail that wags the dog: how the disordered C-terminal domain controls the transcriptional activities of the p53 tumor-suppressor protein. Trends Biochem Sci 41:1022–1034CrossRefGoogle Scholar
  20. Lim S, Koo JH, Choi JM (2016) Use of cell-penetrating peptides in dendritic cell-based vaccination. Immune Netw 16:33–43CrossRefGoogle Scholar
  21. McNamara MG, Sahebjam S, Mason WP (2013) Emerging biomarkers in glioblastoma. Cancers (Basel) 5:1103–1119CrossRefGoogle Scholar
  22. Park SH, Seong MA, Lee HY (2016) p38 MAPK-induced MDM2 degradation confers paclitaxel resistance through p53-mediated regulation of EGFR in human lung cancer cells. Oncotarget 7:8184–8199Google Scholar
  23. Riemenschneider MJ, Jeuken JW, Wesseling P, Reifenberger G (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120:567–584CrossRefGoogle Scholar
  24. Uo T, Kinoshita Y, Morrison RS (2007) Apoptotic actions of p53 require transcriptional activation of PUMA and do not involve a direct mitochondrial/cytoplasmic site of action in postnatal cortical neurons. J Neurosci 27:12198–12210CrossRefGoogle Scholar
  25. Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, Yuan A, Lin CW, Yang SC, Chan WK, Li KC, Hong TM, Yang PC (2009) p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol 11:694–704CrossRefGoogle Scholar
  26. Weathers SS, Gilbert MR (2017) Toward personalized targeted therapeutics: an overview. Neurotherapeutics 14:256–264CrossRefGoogle Scholar
  27. Yamada S, Kanno H, Kawahara N (2012) Trans-membrane peptide therapy for malignant glioma by use of a peptide derived from the MDM2 binding site of p53. J Neurooncol 109:7–14CrossRefGoogle Scholar
  28. Yu J, Guo M, Wang T, Li X, Wang D, Wang X, Zhang Q, Wang L, Zhang Y, Zhao C, Feng B (2016) Inhibition of cell proliferation, migration and invasion by a glioma-targeted fusion protein combining the p53 C terminus and MDM2-binding domain. Cell Prolif 49:79–89CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Dan Wang
    • 1
  • Meihua Guo
    • 1
  • Jiawen Yu
    • 1
  • Xinying Wang
    • 1
  • Qian Zhang
    • 1
  • Xu Yang
    • 1
  • Jiaqi Li
    • 1
  • Chunhui Zhao
    • 2
  • Bin Feng
    • 1
  1. 1.Department of BiotechnologyDalian Medical UniversityDalianChina
  2. 2.College of Life SciencesLiaoning Normal UniversityDalianChina

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