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

TITLE=Vasoactive intestinal peptide–VIPR2 signaling regulates tumor cell migration

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.852358

DOI=10.3389/fonc.2022.852358

ISSN=2234-943X

ABSTRACT=<p>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)P<sub>2</sub> into PI(3,4,5)P<sub>3</sub>. The synthesized PI(3,4,5)P<sub>3</sub> 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 <italic>via</italic> this pathway. We found that silencing of <italic>VIPR2</italic> 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)P<sub>3</sub> was significantly attenuated by <italic>VIPR2</italic>-silencing. <italic>VIPR2</italic>-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, <italic>VIPR2</italic>-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)P<sub>3</sub>.</p>