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

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2023-03, Vol.161, p.170940-170940, Article 170940
• Main Authors: Asano, Satoshi, Ono, Ami, Sakamoto, Kotaro, Hayata-Takano, Atsuko, Nakazawa, Takanobu, Tanimoto, Kotaro, Hashimoto, Hitoshi, Ago, Yukio
• Format: Article
• Language: English
• Subjects: Animals; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; cAMP; Cell Proliferation; ERK; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; GPCR; Humans; MAP Kinase Signaling System; Mice; Receptors, Vasoactive Intestinal Peptide, Type II - metabolism; Signal Transduction; Vasoactive Intestinal Peptide - genetics; Vasoactive Intestinal Peptide - metabolism; VIPR2
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2023.170940

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. •VIPR2 overexpression promotes in vivo tumor growth of breast cancer cells.•Treatment with a VIPR2 antagonist peptide reduces breast cancer cell proliferation.•VIPR2 overexpression causes increases in cAMP and phosphorylated ERK levels.•ERK inactivation abrogates the effect of VIPR2 overexpression on cell proliferation.