Vasoactive intestinal peptide-VIPR2 signaling regulates tumor cell migration

Satoshi Asano; Misa Yamasaka; Kairi Ozasa; Kotaro Sakamoto; Atsuko Hayata-Takano; Takanobu Nakazawa; Hitoshi Hashimoto; James A Waschek; Yukio Ago

doi:10.3389/fonc.2022.852358

Vasoactive intestinal peptide-VIPR2 signaling regulates tumor cell migration

Front Oncol. 2022 Sep 27:12:852358. doi: 10.3389/fonc.2022.852358. eCollection 2022.

Authors

Satoshi Asano^{1

2}, Misa Yamasaka², Kairi Ozasa², Kotaro Sakamoto³, Atsuko Hayata-Takano^{4

5}, Takanobu Nakazawa^{4

6}, Hitoshi Hashimoto^{4

5

7

8

9}, James A Waschek¹⁰, Yukio Ago^{1

2}

Affiliations

¹ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
² School of Dentistry, Hiroshima University, Hiroshima, Japan.
³ Research and Development Department, Ichimaru Pharcos Company Limited, Gifu, Japan.
⁴ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
⁵ 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, Japan.
⁶ Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences, Tokyo University of Agriculture, Tokyo, Japan.
⁷ Division of Bioscience, Institute for Datability Science, Osaka University, Osaka, Japan.
⁸ Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
⁹ Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁰ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, United States.

Abstract

Phosphoinositide metabolism is critically involved in human cancer cell migration and metastatic growth. The formation of lamellipodia at the leading edge of migrating cells is regulated by metabolism of the inositol phospholipid PI(4,5)P₂ into PI(3,4,5)P₃. The synthesized PI(3,4,5)P₃ promotes the translocation of WASP family verprolin homologous protein 2 (WAVE2) to the plasma membrane and regulates guanine nucleotide exchange factor Rac-mediated actin filament remodeling. Here, we investigated if VIPR2, a receptor for vasoactive intestinal peptide (VIP), has a potential role in regulating cell migration via this pathway. We found that silencing of VIPR2 in MDA-MB-231 and MCF-7 human breast cancer cells inhibited VIP-induced cell migration. In contrast, stable expression of exogenous VIPR2 promoted VIP-induced tumor cell migration, an effect that was inhibited by the addition of a PI3-kinase (PI3K)γ inhibitor or a VIPR2-selective antagonist. VIPR2 stably-expressing cells exhibited increased PI3K activity. Membrane localization of PI(3,4,5)P₃ was significantly attenuated by VIPR2-silencing. VIPR2-silencing in MDA-MB-231 cells suppressed lamellipodium extension; in VIPR2-overexpressing cells, VIPR2 accumulated in the cell membrane on lamellipodia and co-localized with WAVE2. Conversely, VIPR2-silencing reduced WAVE2 level on the cell membrane and inhibited the interaction between WAVE2, actin-related protein 3, and actin. These findings suggest that VIP-VIPR2 signaling controls cancer migration by regulating WAVE2-mediated actin nucleation and elongation for lamellipodium formation through the synthesis of PI(3,4,5)P₃.

Keywords: GPCR; VIPR2; breast cancer; cell migration; cytoskeleton; phosphatidylinositol signaling.