Skip to main content

Advertisement

SpringerLink
Log in

Effects of PACAP and VIP on cAMP-generating System and Proliferation of C6 Glioma Cells

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

An identification of PAC1- and VPAC-type receptors in a great number of neoplastic cells gave rise to intensive studies on the biochemical and physiological role of the mentioned peptides in cancers. Our earlier studies focused on effects of pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) in C6 glioma cells have shown their stimulatory receptor-mediated action on the cyclic adenosine monophosphate (cAMP)-generating system. In the present study, we demonstrated that truncated peptides, i.e., PACAP6-38 and VIP6-28, both produced a significant inhibition of the VIP-induced increase in cAMP production, whereas only PACAP6-38 did antagonize the PACAP-38 effect. In contrast to the well-expressed PACAP-38 and VIP effects on cAMP production in C6 cells, helodermin and secretin were poorly active as cAMP stimulators in this cell line, displaying some activity only at a high 5-μM dose. PACAP-38 and, to a lesser extent VIP stimulated the proliferation of C6 glioma cells, which was shown by an increased incorporation of 3H-thymidine into the cells, and the effects of these two peptides were antagonized by PACAP6-38. The truncated PACAP (10 μM) by itself significantly inhibited C6 cell proliferation. The study with the use of forskolin and dibutyryl-cAMP revealed that the growth effects of PACAP were cAMP independent. Our findings suggest that glioma C6 cells possess PAC1- and VPAC-type receptors, but the density of PAC1 seems to be much larger than VPAC receptors. Although the proliferative activity of PACAP and VIP is mediated via the PAC1-type receptor, the signaling cascade underlying this phenomenon does not seem to involve cAMP.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Arimura, A. (1998). Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Japanese Journal of Physiology, 48, 301–331.

    Article  PubMed  CAS  Google Scholar 

  • Bik, W., Wolinska-Witort, E., Pawlak, J., Skwarlo-Sonta, K., et al. (2006). PACAP38 as a modulator of immune and endocrine responses during LPS-induced acute inflammation in rats. Journal of Neuroimmunology, 177, 76–84.

    Article  PubMed  CAS  Google Scholar 

  • Dalsgaard, T., Hannibal, J., Fahrenkrug, J., Larsen, C. R., et al. (2003). VIP and PACAP display different vasodilatory effects in rabbit coronary and cerebral arteries. Regulatory Peptides, 110, 179–188.

    Article  PubMed  CAS  Google Scholar 

  • Dejda, A., Jozwiak-Bebenista, M., & Nowak, J. Z. (2006). PACAP, VIP, and PHI: Effects on AC-, PLC-, and PLD-driven signaling systems in the primary glial cell cultures. Annals of the New York Academy of Sciences, 1070, 220–225.

    Article  PubMed  CAS  Google Scholar 

  • Dufes, C., Alleaume, C., Montoni, A., Olivier, J.-C., et al. (2003). Effects of the vasoactive intestinal peptide (VIP) and relate peptides on glioblastoma cell growth in vitro. Journal of Molecular Neuroscience, 21, 97–108.

    Article  Google Scholar 

  • Dugan, L. L., Kim, J. S., Zhang, Y., Bart, R. D., et al. (1999). Differential effects of cAMP in neurons and astrocytes. Role of b-Raf. Journal of Biological Chemistry, 274, 25842–25848.

    Article  PubMed  CAS  Google Scholar 

  • Fabry, M., Cabrele, C., Hocker, H., & Beck-Sickinger, A. G. (2000). Differently labeled peptide ligands for rapid investigation of receptor expression on a new human glioblastoma cell line. Peptides, 21, 1885–1893.

    Article  PubMed  CAS  Google Scholar 

  • Farini, D., Puglianiello, A., Mammi, C., Siracusa, G., et al. (2003). Dual effect of pituitary adenylate cyclase activating polypeptide on prostate tumor LNCaP cells: Short- and long-term exposure affect proliferation and neuroendocrine differentiation. Endocrinology, 144, 1631–1643.

    Article  PubMed  CAS  Google Scholar 

  • Ghzili, H., Grumolato, L., Vaudry, H., & Anouar, Y. (2006). Possible implication of the transcriptional regulator Id3 in PACAP-induced pro-survival signaling during PC12 cell differentiation. Regulatory Peptides, 137, 89–94.

    Article  PubMed  CAS  Google Scholar 

  • Goursaud, S., Pineau, N., Becq-Giraudon, L., Gressens, P., et al. (2005). Human H9 cells proliferation is differently controlled by vasoactive intestinal peptide or peptide histidine methionine: Implication of a GTP-sensitive form of VPAC1 receptor. Journal of Neuroimmunology, 158, 94–105.

    Article  PubMed  CAS  Google Scholar 

  • Gozes, I., Fridkin, M., Hill, J. M., & Brenneman, D. E. (1999). Pharmaceutical VIP: Prospects and problems. Current Medicinal Chemistry, 6, 1019–1034.

    PubMed  CAS  Google Scholar 

  • Harmar, A. J., Arimura, A., Gozes, I., Journot, L., et al. (1998). International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacological Reviews, 50, 265–270.

    PubMed  CAS  Google Scholar 

  • Heraud, C., Hilairet, S., Muller, J. M., Leterrier, J. F., et al. (2004). Neuritogenesis induced by vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and peptide histidine methionine in SH-SY5y cells is associated with regulated expression of cytoskeleton mRNAs and proteins. Journal of Neuroscience Research, 75, 320–329.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kurino, M., Fukunaga, K., Ushio, Y., & Miyamoto, E. (1996). Cyclic AMP inhibits activation of mitogen-activated protein kinase and cell proliferation in response to growth factors in cultured rat cortical astrocytes. Journal of Neurochemistry, 67, 2246–2255.

    Article  PubMed  CAS  Google Scholar 

  • Laburthe, M., Couvineau, A., & Tan, V. (2007). Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides, 28, 1631–1639.

    Article  PubMed  CAS  Google Scholar 

  • Le, S. V., Yamaguchi, D. J., McArdle, C. A., Tachiki, K., et al. (2002). PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human colonic tumor cells. Regulatory Peptides, 109, 115–125.

    Article  PubMed  CAS  Google Scholar 

  • Lelievre, V., Meunier, A. C., Caigneaux, E., Falcon, J., et al. (1998a). Differential expression and function of PACAP and VIP receptors in four human colonic adenocarcinoma cell lines. Cellular Signaling, 10, 13–26.

    Article  CAS  Google Scholar 

  • Lelievre, V., Pineau, N., Du, J., Wen, C. H., et al. (1998b). Differential effects of peptide histidine isoleucine (PHI) and related peptides on stimulation and suppression of neuroblastoma cell proliferation. Journal of Biological Chemistry, 273, 19685–19690.

    Article  PubMed  CAS  Google Scholar 

  • Leyton, J., Coelho, T., Coy, D. H., Jakolew, S., et al. (1998). PACAP(6-38) inhibits the growth of prostate cancer cells. Cancer Letters, 125, 131–139.

    Article  PubMed  CAS  Google Scholar 

  • Leyton, J., Gozes, Y., Pisegna, J., Coy, D., et al. (1999). PACAP(6-38) is a PACAP receptor antagonist for breast cancer cells. Breast Cancer Research and Treatment, 56, 177–186.

    Article  PubMed  CAS  Google Scholar 

  • Lu, N., Zhou, R., & DiCicco-Bloom, E. (1998). Opposing mitogenic regulation by PACAP in sympathetic and cerebral cortical precursors correlates with differential expression of PACAP receptor (PAC1-R) isoforms. Journal of Neuroscience Research, 53, 651–662.

    Article  PubMed  CAS  Google Scholar 

  • Monaghan, T. K., Mackenzie, C. J., Plevin, R., & Lutz, E. M. (2008). PACAP-38 induces neuronal differentiation of human SH-SY5Y neuroblastoma cells via cAMP-mediated activation of ERK and p38 MAP kinase. Journal of Neurochemistry, 104, 74–88.

    PubMed  CAS  Google Scholar 

  • Moody, T. W., Hill, J. M., & Jensen, R. T. (2003). VIP as a trophic factor in the CNS and cancer cells. Peptides, 24, 163–177.

    Article  PubMed  CAS  Google Scholar 

  • Nicot, A., & DiCicco-Bloom, E. (2001). Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression. Proceedings of the National Academy of Sciences, 98, 4758–4763.

    Article  CAS  Google Scholar 

  • Nowak, J. Z., & Zawilska, J. B. (2003). PACAP in avians: Origin, occurrence, and receptors—Pharmacological and functional considerations. Current Pharmaceutical Design, 9, 465–481.

    Article  Google Scholar 

  • Nussdorfer, G. G., & Malendowicz, L. K. (1998). Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo-pituitary–adrenal axis. Peptides, 19, 1443–1467.

    Article  PubMed  CAS  Google Scholar 

  • Reubi, J. C., Laderach, U., Waser, B., Gebbers, J. O., et al. (2000). Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Research, 60, 3105–3112.

    PubMed  CAS  Google Scholar 

  • Salomon, Y., Londos, C., & Rodbell, M. (1974). A highly sensitive adenylate cyclase assay. Analytical Biochemistry, 58, 541–544.

    Article  PubMed  CAS  Google Scholar 

  • Schulz, S., Rocken, C., Mawrin, C., Weise, W., et al. (2004). Immunocytochemical identification of VPAC1, VPAC2, and PAC1 receptors in normal and neoplastc human tissues with subtype-specific antibodies. Clinical Cancer Research, 10, 8235–8242.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, A., Walters, J., Gozes, Y., Fridkin, M., et al. (2001). A vasoactive intestinal peptide antagonist inhibits growth of glioblastoma cells. Journal of Molecular Neuroscience, 17, 331–339.

    Article  PubMed  CAS  Google Scholar 

  • Shimizu, H., Daly, J. W., & Creveling, C. R. (1969). A radioisotopic method for measuring the formation of adenosine 3′, 5′-cyclic monophosphate in incubated slices of brain. Journal of Neurochemistry, 16, 1609–1619.

    Article  PubMed  CAS  Google Scholar 

  • Sokolowska, P., & Nowk, J. Z. (2006). Cyclic AMP formation in C6 glioma cells: effect of PACAP and VIP in early and late passages. Annals of the New York Academy of Sciences, 1070, 566–569.

    Article  PubMed  CAS  Google Scholar 

  • Vallejo, I., & Vallejo, M. (2002). Pituitary adenylate cyclase-activating polypeptide induces astrocyte differentiation of precursor cells from developing cerebral cortex. Molecular and Cellular Neuroscience, 21, 671–683.

    Article  PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Yon, L., et al. (2000). Pituitary adenylate cyclase-activating polypeptide and its receptors: From structure to functions. Pharmacological Reviews, 52, 269–324.

    PubMed  CAS  Google Scholar 

  • Vertongen, P., Camby, I., Darro, F., Kiss, R., et al. (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  PubMed  CAS  Google Scholar 

  • Waschek, J. A. (2002). Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Developmental Neuroscience, 24, 14–23.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Medical Biology, Polish Academy of Sciences, Lodz, 93-232, Poland

    Paulina Sokolowska & Jerzy Z. Nowak

  2. Department of Pharmacology, Medical University of Lodz, Lodz, Poland

    Jerzy Z. Nowak

Authors
  1. Paulina Sokolowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerzy Z. Nowak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paulina Sokolowska.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sokolowska, P., Nowak, J.Z. Effects of PACAP and VIP on cAMP-generating System and Proliferation of C6 Glioma Cells. J Mol Neurosci 36, 286–291 (2008). https://doi.org/10.1007/s12031-008-9071-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-008-9071-9

Keywords

Search

Navigation