Skip to main content
SpringerLink
Log in

Neuropeptides of the VIP family inhibit glioblastoma cell invasion

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides acting through VPAC1, VPAC2 and PAC1 receptors (referred here as the VIP-receptor system). In the central nervous system, VIP and PACAP are involved in neurogenesis, cell differentiation and migration, suggesting that they could be implicated in the development of glioblastoma (GBM). The infiltrative nature of GBM remains a major problem for the therapy of these tumors. We previously demonstrated that the VIP-receptor system regulated cell migration of the human cell lines M059J and M059K, derived from a single human GBM. Here, we evaluated the involvement of the VIP-receptor system in GBM cell invasion. In Matrigel invasion assays, M059K cells that express more the VIP-receptor system than M059J cells were less invasive. Invasion assays performed in the presence of agonists, antagonists or anti-PACAP antibodies as well as experiments with transfected M059J cells overexpressing the VPAC1 receptor indicated that the more the VIP-receptor system was expressed and activated, the less the cells were able to invade. Western immunoblotting experiments revealed that the VIP-receptor system inactivated the signaling protein AKT. Invasion assays carried out in the presence of an AKT inhibitor demonstrated the involvement of this signaling kinase in the regulation of cell invasion by the VIP-receptor system in M059K cells. The inhibition by VIP of invasion and AKT was also observed in U87 cells. In conclusion, VIP and PACAP act as anti-invasive factors in different GBM cell lines, a function mediated by VPAC1 inhibition of AKT signaling in M059K cells.

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

Similar content being viewed by others

References

  1. Dunn GP, Rinne ML, Wykosky J et al (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26:756–784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci CMLS 64:458–478

    Article  CAS  Google Scholar 

  3. Dickson L, Finlayson K (2009) VPAC and PAC receptors: from ligands to function. Pharmacol Ther 121:294–316

    Article  CAS  PubMed  Google Scholar 

  4. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol 166:4–17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Robberecht P, Woussen-Colle MC, Vertongen P, De Neef P, Hou X, Salmon I, Brotchi J (1994) Expression of pituitary adenylate cyclase activating polypeptide (PACAP) receptors in human glial cell tumors. Peptides 15:661–665

    Article  CAS  PubMed  Google Scholar 

  6. Reubi JC (1995) In vitro identification of vasoactive intestinal peptide receptors in human tumors: implications for tumor imaging. J Nucl Med Off Publ Soc Nucl Med 36:1846–1853

    CAS  Google Scholar 

  7. Vertongen P, Camby I, Darro F, Kiss R, Robberecht P (1996) VIP and pituitary adenylate cyclase activating polypeptide (PACAP) have an antiproliferative effect on the T98G human glioblastoma cell line through interaction with VIP2 receptor. Neuropeptides 30:491–496

    Article  CAS  PubMed  Google Scholar 

  8. Jaworski DM (2000) Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) and the PACAP-selective receptor in cultured rat astrocytes, human brain tumors, and in response to acute intracranial injury. Cell Tissue Res 300:219–230

    Article  CAS  PubMed  Google Scholar 

  9. Sharma A, Walters J, Gozes Y, Fridkin M, Brenneman D, Gozes I, Moody TW (2001) A vasoactive intestinal peptide antagonist inhibits the growth of glioblastoma cells. J Mol Neurosci MN 17:331–339

    Article  CAS  Google Scholar 

  10. Dufes C, Alleaume C, Montoni A, Olivier J-C, Muller J-M (2003) Effects of the vasoactive intestinal peptide (VIP) and related peptides on glioblastoma cell growth in vitro. J Mol Neurosci MN 21:91–102

    Article  CAS  Google Scholar 

  11. Cochaud S, Chevrier L, Meunier A-C, Brillet T, Chadéneau C, Muller J-M (2010) The vasoactive intestinal peptide-receptor system is involved in human glioblastoma cell migration. Neuropeptides 44:373–383

    Article  CAS  PubMed  Google Scholar 

  12. Masmoudi-Kouki O, Gandolfo P, Castel H, Leprince J, Fournier A, Dejda A, Vaudry H, Tonon M-C (2007) Role of PACAP and VIP in astroglial functions. Peptides 28:1753–1760

    Article  CAS  PubMed  Google Scholar 

  13. Cameron DB, Galas L, Jiang Y, Raoult E, Vaudry D, Komuro H (2007) Cerebellar cortical-layer-specific control of neuronal migration by pituitary adenylate cyclase-activating polypeptide. Neuroscience 146:697–712

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Allalunis-Turner MJ, Barron GM, Day RS 3rd, Dobler KD, Mirzayans R (1993) Isolation of two cell lines from a human malignant glioma specimen differing in sensitivity to radiation and chemotherapeutic drugs. Radiat Res 134:349–354

    Article  CAS  PubMed  Google Scholar 

  15. Wang H, Wang H, Zhang W, Huang HJ, Liao WSL, Fuller GN (2004) Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Investig J Tech Methods Pathol 84:941–951

    Article  CAS  Google Scholar 

  16. Joy AM, Beaudry CE, Tran NL, Ponce FA, Holz DR, Demuth T, Berens ME (2003) Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. J Cell Sci 116:4409–4417

    Article  CAS  PubMed  Google Scholar 

  17. Kleber S, Sancho-Martinez I, Wiestler B et al (2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13:235–248

    Article  CAS  PubMed  Google Scholar 

  18. Miao H, Li D-Q, Mukherjee A et al (2009) EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16:9–20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Kwiatkowska A, Kijewska M, Lipko M, Hibner U, Kaminska B (2011) Downregulation of Akt and FAK phosphorylation reduces invasion of glioblastoma cells by impairment of MT1-MMP shuttling to lamellipodia and downregulates MMPs expression. Biochim Biophys Acta 1813:655–667

    Article  CAS  PubMed  Google Scholar 

  20. Natsume A, Kato T, Kinjo S et al (2012) Girdin maintains the stemness of glioblastoma stem cells. Oncogene 31:2715–2724

    Article  CAS  PubMed  Google Scholar 

  21. Stambolic V, Woodgett JR (2006) Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol 16:461–466

    Article  CAS  PubMed  Google Scholar 

  22. Kwiatkowska A, Symons M (2013) Signaling determinants of glioma cell invasion. Adv Exp Med Biol 986:121–141

    Article  CAS  PubMed  Google Scholar 

  23. Qiao M, Sheng S, Pardee AB (2008) Metastasis and AKT activation. Cell Cycle Georget Tex 7:2991–2996

    Article  CAS  Google Scholar 

  24. Koul D, Parthasarathy R, Shen R, Davies MA, Jasser SA, Chintala SK, Rao JS, Sun Y, Benvenisite EN, Liu TJ, Yung WK (2001) Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20:6669–6678

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi S, Yamada-Okabe H, Hamada K, Ohta S, Kawase T, Yoshida K, Toda M (2011) Downregulation of uPARAP mediates cytoskeletal rearrangements and decreases invasion and migration properties in glioma cells. J Neurooncol 103:267–276

    Article  PubMed  Google Scholar 

  26. Balster DA, O’Dorisio MS, Albers AR, Park SK, Qualman SJ (2002) Suppression of tumorigenicity in neuroblastoma cells by upregulation of human vasoactive intestinal peptide receptor type 1. Regul Pept 109:155–165

    Article  CAS  PubMed  Google Scholar 

  27. May V, Lutz E, MacKenzie C, Schutz KC, Dozark K, Braas KM (2010) Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem 285:9749–9761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Mei FC, Qiao J, Tsygankova OM, Meinkoth JL, Quilliam LA, Cheng X (2002) Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation. J Biol Chem 277:11497–11504

    Article  CAS  PubMed  Google Scholar 

  29. Nijholt IM, Dolga AM, Ostroveanu A, Luiten PGM, Schmidt M, Eisel ULM (2008) Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation. Cell Signal 20:1715–1724

    Article  CAS  PubMed  Google Scholar 

  30. Higuchi M, Masuyama N, Fukui Y, Suzuki A, Gotoh Y (2001) Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells. Curr Biol CB 11:1958–1962

    Article  CAS  Google Scholar 

  31. Fernández-Martínez AB, Bajo AM, Sánchez-Chapado M, Prieto JC, Carmena MJ (2009) Vasoactive intestinal peptide behaves as a pro-metastatic factor in human prostate cancer cells. Prostate 69:774–786

    Article  PubMed  Google Scholar 

  32. Fernández-Martínez AB, Bajo AM, Isabel Arenas M, Sánchez-Chapado M, Prieto JC, Carmena MJ (2010) Vasoactive intestinal peptide (VIP) induces malignant transformation of the human prostate epithelial cell line RWPE-1. Cancer Lett 299:11–21

    Article  PubMed  Google Scholar 

  33. Ogasawara M, Murata J, Ayukawa K, Saiki I (1997) Differential effect of intestinal neuropeptides on invasion and migration of colon carcinoma cells in vitro. Cancer Lett 119:125–130

    Article  CAS  PubMed  Google Scholar 

  34. Vacas E, Arenas MI, Muñoz-Moreno L, Bajo AM, Sánchez-Chapado M, Prieto JC, Carmena MJ (2013) Antitumoral effects of vasoactive intestinal peptide in human renal cell carcinoma xenografts in athymic nude mice. Cancer Lett 336:196–203

    Article  CAS  PubMed  Google Scholar 

  35. Hoyer D, Bartfai T (2012) Neuropeptides and neuropeptide receptors: drug targets, and peptide and non-peptide ligands: a tribute to Prof Dieter Seebach. Chem Biodivers 9:2367–2387

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Marianne Bernard for her help in the preparation of plasmid stocks in bacteria and Pr L. Karayan, Université de Poitiers, who kindly provided the M059J and M059K cells. This work was supported by grants from the ‘‘Institut National du Cancer (INCA), Cancéropôle Grand-Ouest”, from the ‘‘Ligue contre le Cancer du Grand-Ouest, comité de la Vienne et comité des Deux-Sèvres” and from the “Lions Club de Melle”. Stéphanie Cochaud and Souheyla Bensalma were recipients of Ph.D. fellowships from the French ‘‘Ministère de l’enseignement supérieur et de la recherche” and from the « Région Poitou–Charentes», respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Equipe émergente « Récepteurs, régulations et cellules tumorales » (2RCT), Université de Poitiers, 1 rue Georges Bonnet, TSA 51106, 86073, Poitiers Cedex 9, France

    Stéphanie Cochaud, Souheyla Bensalma, Jean-Marc Muller & Corinne Chadéneau

  2. ERL CNRS/Université de Poitiers n° 7368, 1 Rue Georges Bonnet, TSA 51106, 86073, Poitiers Cedex 9, France

    Annie-Claire Meunier & Arnaud Monvoisin

Authors
  1. Stéphanie Cochaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annie-Claire Meunier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnaud Monvoisin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Souheyla Bensalma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Marc Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Corinne Chadéneau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Corinne Chadéneau.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cochaud, S., Meunier, AC., Monvoisin, A. et al. Neuropeptides of the VIP family inhibit glioblastoma cell invasion. J Neurooncol 122, 63–73 (2015). https://doi.org/10.1007/s11060-014-1697-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1697-6

Keywords

Search

Navigation