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The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.

ABSTRACT: Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu₁-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca²⁺ mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu₁-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC7970304 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.

Jiang Yunlu Y Yan Maocai M Wang Chunmei C Wang Qinqin Q Chen Xiaoyu X Zhang Rumin R Wan Lei L Ji Bingyuan B Dong Bo B Wang Huiyun H Chen Jing J

Frontiers in pharmacology 20210304

Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu<sub>1</sub>-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the ...[more]

PMID: 33746758

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Project description:Cancer‑associated fibroblasts (CAFs) are pivotal in tumor progression. TP53‑deficiency in cancer cells is associated with robust stromal activation. The apelin‑apelin receptor (APJ) system has been implicated in suppressing fibroblast‑to‑myofibroblast transition in non‑neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin‑APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53‑wild colon cancer, HCT116, and Caco‑2; TP53‑mutant colon cancer, SW480, and DLD‑1; and colon fibroblasts, CCD‑18Co), resected human tissue samples of colorectal cancers, and immune‑deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co‑cultured with p53‑suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ‑suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast‑like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma‑ and Mad‑related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ‑suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR‑5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell‑derived exosomes induced CAF‑like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.

Dataset Information

The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.

Publications

The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.

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