Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway

Satoshi Asano; Ami Ono; Kotaro Sakamoto; Atsuko Hayata-Takano; Takanobu Nakazawa; Kotaro Tanimoto; Hitoshi Hashimoto; Yukio Ago

doi:10.1016/j.peptides.2023.170940

Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway

Peptides. 2023 Mar:161:170940. doi: 10.1016/j.peptides.2023.170940. Epub 2023 Jan 2.

Authors

Satoshi Asano¹, Ami Ono², Kotaro Sakamoto³, Atsuko Hayata-Takano⁴, Takanobu Nakazawa⁵, Kotaro Tanimoto⁶, Hitoshi Hashimoto⁷, Yukio Ago⁸

Affiliations

¹ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan. Electronic address: sasano@hiroshima-u.ac.jp.
² Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan; Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
³ Research & Development Department, Ichimaru Pharcos Company Limited, 318-1 Asagi, Motosu, 501-0475 Gifu, Japan.
⁴ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Osaka 565-0871, Japan.
⁵ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
⁶ Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
⁷ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Osaka 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, Osaka 565-0871, Japan; Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
⁸ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan. Electronic address: yukioago@hiroshima-u.ac.jp.

PMID: 36603770
DOI: 10.1016/j.peptides.2023.170940

Abstract

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a class B G protein-coupled receptor with the neuropeptide VIP as a ligand. Increased VIPR2 mRNA expression and/or VIPR2 gene copy number has been documented in several cancers including breast carcinoma. However, the pathophysiological role of increased VIPR2 in the proliferation of breast cancer cells remains largely unknown. In this study, we found that VIPR2 overexpression in MCF-7 and MDA-MB-231 cells, human breast cancer cell lines, promoted cell proliferation. Increased VIPR2 also exacerbated intraperitoneal proliferation of breast cancer MDA-MB-231 cells in a tumor nude mouse model in vivo. Treatment with KS-133, a VIPR2-selective antagonist peptide, significantly inhibited VIP-induced cell proliferation in VIPR2-overexpressing MCF-7 and MDA-MB-231 cells. Overexpressed VIPR2 caused increases in the levels of cAMP and phosphorylated extracellular signal-regulated kinase (ERK), which involves a VIPR2 signaling pathway through Gs protein. Additionally, phosphorylation of vasodilator-stimulated phosphoprotein (Ser157) and cAMP response element binding protein (Ser133) in VIPR2-overexpressing MCF-7 cells was greater than that in control cells, suggesting the increased PKA activity. Moreover, an inhibitor of mitogen-activated protein kinase kinase, U0126, attenuated tumor proliferation in exogenous VIPR2-expressing MCF-7 and MDA-MB-231 cells at the same level as observed in EGFP-expressing cells treated with U0126. Together, these findings suggest that VIPR2 controls breast tumor growth by regulating the cAMP/PKA/ERK signaling pathway, and the excessive expression of VIPR2 may lead to an exacerbation of breast carcinoma.

Keywords: Breast cancer; Cell proliferation; ERK; GPCR; VIPR2; cAMP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases* / genetics
Extracellular Signal-Regulated MAP Kinases* / metabolism
Female
Humans
MAP Kinase Signaling System
Mice
Receptors, Vasoactive Intestinal Peptide, Type II* / metabolism
Signal Transduction
Vasoactive Intestinal Peptide / genetics
Vasoactive Intestinal Peptide / metabolism

Substances

Extracellular Signal-Regulated MAP Kinases
Receptors, Vasoactive Intestinal Peptide, Type II
U 0126
Vasoactive Intestinal Peptide
Vipr2 protein, mouse
VIPR2 protein, human