VIP as a trophic factor in the CNS and cancer cells

doi:10.1016/S0196-9781(02)00290-5

Peptides

Volume 24, Issue 1, January 2003, Pages 163-177

https://doi.org/10.1016/S0196-9781(02)00290-5 Get rights and content

Abstract

The effects of vasoactive intestinal peptide (VIP) on the proliferation of central nervous system (CNS) and cancer cells were investigated. VIP has important actions during CNS development. During neurogenesis, VIP stimulates the proliferation and differentiation of brain neurons. Addition of VIP to embryonic mouse spinal cord cultures increases neuronal survival and activity dependent neurotrophic factor (ADNF) secretion from astroglial cells. VIP is an integrative regulator of brain growth and development during neurogenesis and embryogenesis. Also, VIP causes increased proliferation of human breast and lung cancer cells in vitro. VIP binds with high affinity to cancer cells, elevates the cAMP and increases gene expression of c-fos, c-jun, c-myc and vascular endothelial cell growth factor. The effects of VIP on cancer cells are reversed by VIPhybrid, a synthetic VPAC₁ receptor antagonist. VIPhyb inhibits the basal growth of lung cancer cells in vitro and tumors in vivo and potentiates the ability of chemotherapeutic drugs to kill cancer cells. Due to the high density of VPAC₁ receptors in cancer cells, VIP has been radiolabeled with $^{123} I$ , $^{18} F$ and $^{99m} Tc$ to image tumors. It remains to be determined if radiolabeled VIP analogs will be useful agents for early detection of cancer in patients.

Introduction

VIP is a 28 amino acid peptide initially isolated on its ability to cause vasodilation of blood vessels [147]. It is structurally similar to the 27 amino acid pituitary adenylate cyclase activating polypeptide (PACAP) [2], [109]. Both VIP and PACAP bind with high affinity to VPAC₁ receptors, which are present in high densities (100,000/cell) on the surface of breast and lung cancer cells [43], [90], [150]. VIP stimulates, whereas the VPAC₁ receptor blocker VIPhybrid (VIPhyb) inhibits the clonal growth of breast and lung cancer cells [117], [186].

VIP is biologically active in the central nervous system. VIP neurons are present in the cortex where they colocalize with the neurotransmitter acetylcholine [4], [103]. VIP elevates cAMP levels and stimulates adenylyl cyclase in the cortex, striatum, hypothalamus, hippocampus, thalamus and midbrain of the rat [25], [33], [140]. VIP caused glycogenolysis in the cortex, and causes vasodilation of isolated cerebral arteries [31], [104], [105]. VIP enhances survival of embryonic mouse spinal cord neurons in culture [9]. VIP produced neuroprotection as a result of secretion of activity dependent neurotrophic factor (ADNF) and other cytokines from astroglia [10]. PACAP can rescue neurons from apoptotic death and glutamate toxicity [29]. In particular, PACAP inhibits the activation of caspase-3 in cerebellar granule cells [172]. It remains to be determined if the neuroprotective effects of VIP-like peptide may be useful in the treatment of neurodegenerative diseases such as Alzheimer’s and/or Parkinson’s disease [51], [56], [130].

The actions of VIP and PACAP are mediated by G-protein coupled receptors [73]. The human VPAC₁ receptor is a 457 amino acid glycoprotein which crosses the plasma membrane seven times [79]. It is structurally similar to the VPAC₂ and PAC₁ receptors which bind VIP with high and low affinity respectively [1], [66], [101], [138], [154]; in contrast PACAP binds with high affinity to VPAC₁, VPAC₂ and PAC₁ receptors (Table 1). Fig. 1 shows that the activated VPAC₁ receptor may interact with a stimulatory guanine nucleotide binding protein (Gs), which activates adenylyl cyclase [32], [86], [163]. The addition of 10 nM VIP to human breast or lung cancer cells increases the cAMP 10–30-fold. The elevated cAMP may activate protein kinase A resulting in increased phosphorylation of protein substrates such as CREB [75]. When CREB is phosphorylated in the nucleus, it alters gene expression [181]. VIP causes increased expression of c-fos, c-jun and c-myc oncogenes. After translation, the c-fos and c-jun proteins may form heterodimers and activate AP-1 sites on the 5′ regulatory region of growth factor genes. VIP alters expression of microtubule associated proteins [87] and increases expression of the vascular endothelial cell growth factor (VEGF) gene in lung cancer cell line NCI-H157 [17]. Also, VIP caused secretion of VEGF from lung cancer cells and increased proliferation of lung cancer cells. Here the trophic effects of VIP in the CNS and cancer cells are reviewed.

Section snippets

VIP/PACAP-like peptides

VIP is synthesized as a high molecular weight precursor protein [49]. The 170 amino acid preproVIP is metabolized by a signal peptidase in the endoplasmic reticulum to yield the 148 amino acid proVIP. ProVIP is cleaved by prohormone convertases to VIP-GKR (preproVIP125–155) and PHM-GKR (preproVIP81–110) [6]. VIP-GKR and PHM-GKR is then cleaved by carboxypeptidase-B like enzymes to VIP-G and PHM-G [80]. The VIP-G and PHM-G can then be metabolized by PAM enzymes to VIP and PHM which have an

VIP receptors

VIP and related peptides can interact with six classes of receptors including the glucagon-like peptide I (GLP-I), GRF, PAC₁, secretin, VPAC₁ and VPAC₂ receptors [1], [66], [77], [101], [138], [154], [165], [166], [168], [170], [175]. The human VPAC₁ receptor contains 457 and is a member of the G-protein-coupled seven transmembrane superfamily. Numerous amino acids in the receptor have been identified which are essential for high affinity VIP binding including Lys¹⁹⁵, Gln²⁰⁷, Cys²⁰⁸, Gly²¹¹ and

Second messengers

Addition of 100 nM VIP to VPAC₁ receptor containing cells elevates the cAMP 10–30-fold within a minute. Fig. 1 shows that the cAMP increase caused by VIP activates protein kinase A leading to phosphorylation of protein substrates. When CREB is phosphorylated, nuclear oncogene expression is increased. Addition of VIP to NCI-H1299 cells increases c-fos mRNA expression three-fold after 1 h. Also, there is a two-fold increase in c-myc mRNAs and 1.5-fold increase in c-jun mRNAs. After translation the

Cancer growth

VIP and PACAP stimulate the growth of lung cancer cells. VIP (1 μM) slightly and 10 nM VIP strongly increased colony formation of SCLC and NSCLC cells. In contrast, higher doses of VIP e.g. 100 nM were ineffective, possibly due to receptor desensitization and/or down-regulation [118].Because VIP and PACAP are autocrine growth factors for breast and lung cancer cells, addition of VIP receptor antagonists inhibits basal cellular proliferation. Using VIPhyb, which blocks both VPAC₁, VPAC₂ and PAC₁

Neuronal development

Similar to other neurotrophic molecules, the neuropeptide VIP exhibits dual roles in the CNS. VIP-like peptides have important actions during CNS development, but also has potent neuroprotective actions and is up-regulated in neuronal injury [53], [82], [110]. During neurogenesis, VIP can stimulate the proliferation, differentiation, neurite outgrowth and survival of neurons. In addition, VIP has been shown to be an integrative regulator of growth and development during embryogenesis [173].

Embyonic growth

VIP has been shown to be an important regulator of embryonic growth in the early post-implantation period of rodent embryogenesis [27], [61], [62], [63], [64], [65], [68], [69], [71], [72], [155], [184]. Treatment of whole cultured embryonic day (E) 9.5 mice with VIP resulted in a dose-related increase in growth as measured by somite number, DNA and protein contents and cross sectional area [61]. The growth stimulatory effects of VIP are attributed to a shortening of the G1 and S phases of the

Summary

VIP is a trophic factor in the CNS and cancer cells. In lung and breast cancer, VIP and PACAP function as autocrine growth factors. The cancer cells have mRNA for preproVIP as well as VIP and PACAP-like immunoreactivity. VIP binds with high affinity to VPAC₁ receptors on lung and breast cancer cells and stimulates adenylyl cyclase. PACAP binds with high affinity to VPAC₁ as well as PAC₁ receptors on lung cancer cells and stimulates adenylyl cyclase as well as MAP kinase activity. Both VIP and

Acknowledgements

The authors thank the many researchers who participated in these studies over the years including Drs. D. Brenneman, I. Gozes, Y. Gozes, J. Leyton and F. Zia.

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Embryonic bone development is a complicated procedure and modulated by neuro-osteogenic interaction. Vasoactive intestinal peptide (VIP) was first identified as a neural vasodilator and further proved to possess multiple biological functions such as neurotransmitter and immune regulator. However, as a key peptide regulator presented in skeletal nerve fibers, the function of VIP on innervation and early bone development regulation has not fully been uncovered yet. In this study, the chick embryo has been used as an experimental model to address the effect of VIP on embryonic bone development. Our study results confirmed the innervation of peripheral nerve fibers into limb bone tissue, which was revealed by the detection of neurofilament (NF) and class III β-tubulin (TUJ-1) in bone tissue at various developing stages. The VIP mRNA and peptide expression level in bone tissue were also increased upon innervation progress. A chick embryonic chemical sympathectomy model was constructed by exposing chick embryos with neurotoxin 6-OHDA. The 6-OHDA exposure of the early chick embryo caused the reduction of neural crest formation and NF expression. 6-OHDA treatment also inhibited distal limb bone development as well as VIP expression. Furthermore, co-application of VIP with 6-OHDA exposure could rescue the inhibited osteogenesis activity and delayed bone development during embryogenesis. Taken together, these results reveal that VIP played an important role during innervation at early stage of bone development. VIP could restore chemical sympathectomy induced osteogenesis inhibition and bone development impair in chick embryos.
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Vasoactive intestinal peptide (VIP) is a member of the pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, and glucagon peptide family. In the nervous system, VIP is expressed by neurons where this neuropeptide, through specific membrane receptors: VPAC receptors (VPAC1 and VPAC2) showing similar affinities for VIP and PACAP, and PAC1 receptor having higher affinity for PACAP than VIP, exert pleiotropic effects including those on immunomodulation, muscle relaxation, cell proliferation and differentiation (Brenneman, 2007; Moody et al., 2003). Several studies have documented a robust neuroprotection of VIP in a variety of brain injury models (Brenneman, 2007; Moody et al., 2003; Yang et al., 2011) and a proangiogenic role in ischemic insult in vitro and in vivo (Yang et al., 2009, 2013).
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ReviewVIP as a trophic factor in the CNS and cancer cells

Abstract

Introduction

Section snippets

VIP/PACAP-like peptides

VIP receptors

Second messengers

Cancer growth

Neuronal development

Embyonic growth

Summary

Acknowledgements

Brain Res.

Lancet

Brain Res.

Int. J. Dev. Neurosci.

Lung Cancer

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Devel. Biol.

Eur. J. Pharmacol.

Life Sci.

Biochem. Biophys. Res. Commun.

Peptides

Peptides

Eur. J. Pharmacol.

Peptides

Brain Res.

FEBS Lett.

FEBS Lett.

Neuron

Peptides

Neuroscience

Neuroscience

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Neuron

Cell Biol.

Peptides

Peptides

Peptides

J. Biol. Chem.

Cancer Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Devel. Brain Res.

Peptides

Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research

Regul. Peptides

Identification of VIP/PACAP receptors on astrocytes using antisense oligodeoxynucleotides

J. Mol. Neurosci.

Regulation of preotease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors

J. Neurosci.

Design and development of a vasoactive intestinal peptide analog as a novel therapeutic for bronchial asthma

Biopolymers

Vasoactive intestinal peptide and electrical activity influence neuronal survival

Proc. Natl. Acad. Sci. USA

A femtomolar-acting neuroprotective peptide

J. Clin. Invest.

Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide

J. Cell Biol.

Vasoactive intestinal peptide: a neurotrophic releasing agent and an astroglial mitogen

J. Neurosci. Res.

Cytokine regulation of neuronal survival

J. Neurochem.

Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide

Nature

Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons

Mol. Pharmacol.

Review
VIP as a trophic factor in the CNS and cancer cells