Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells

Satoshi Asano; Ami Ono; Kaede Baba; Teru Uehara; Kotaro Sakamoto; Atsuko Hayata-Takano; Takanobu Nakazawa; Souichi Yanamoto; Kotaro Tanimoto; Hitoshi Hashimoto; Yukio Ago

doi:10.1016/j.jphs.2024.01.002

Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells

J Pharmacol Sci. 2024 Mar;154(3):139-147. doi: 10.1016/j.jphs.2024.01.002. Epub 2024 Jan 5.

Authors

Affiliations

¹ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; School of Dentistry, 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 School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan.
⁴ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
⁵ Research & Development Department, Ichimaru Pharcos Company Limited, 318-1 Asagi, Motosu, Gifu, 501-0475, Japan.
⁶ Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, 565-0871, Japan; 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, University of Fukui, Osaka, 565-0871, Japan.
⁷ 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.
⁸ School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
⁹ School of Dentistry, 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.
¹⁰ 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, 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.
¹¹ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan. Electronic address: yukioago@hiroshima-u.ac.jp.

PMID: 38395514
DOI: 10.1016/j.jphs.2024.01.002

Abstract

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate various downstream signaling molecules, such as protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and phospholipase C. In this study, we examined the role of VIPR2 in cell cycle progression. KS-133, a newly developed VIPR2-selective antagonist peptide, attenuated VIP-induced cell proliferation in MCF-7 cells. The percentage of cells in the S-M phase was decreased in MCF-7 cells treated with KS-133. KS-133 in the presence of VIP decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and glycogen synthase kinase-3β (GSK3β), resulting in a decrease in cyclin D1 levels. In MCF-7 cells stably-expressing VIPR2, KS-133 decreased PI3K activity and cAMP levels. Treatment with the ERK-specific kinase (MEK) inhibitor U0126 and the class I PI3K inhibitor ZSTK474 decreased the percentage of cells in the S phase. KS-133 reduced the percentage of cells in the S phase more than treatment with U0126 or ZSTK474 alone and did not affect the effect of the mixture of these inhibitors. Our findings suggest that VIPR2 signaling regulates cyclin D1 levels through the cAMP/PKA/ERK and PI3K/AKT/GSK3β pathways, and mediates the G1/S transition to control cell proliferation.

Keywords: Cell cycle; Cell proliferation; Cyclin D; GPCR; VIPR2.

MeSH terms

Butadienes*
Cell Division
Cell Proliferation
Cyclin D1* / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Glycogen Synthase Kinase 3 beta
Humans
MCF-7 Cells
Nitriles*
Peptides, Cyclic*
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
Receptors, Vasoactive Intestinal Peptide, Type II

Substances

U 0126
Cyclin D1
Proto-Oncogene Proteins c-akt
Receptors, Vasoactive Intestinal Peptide, Type II
Phosphatidylinositol 3-Kinases
KS-133
Glycogen Synthase Kinase 3 beta
Extracellular Signal-Regulated MAP Kinases
Phosphatidylinositol 3-Kinase
VIPR2 protein, human
Butadienes
Nitriles
Peptides, Cyclic