論文 - 詳細
| RRC ID | 89148 |
|---|---|
| 著者 | Ju N, Hayashi H, Chang C, Nakagami H, Morishita R, Shimamura M. |
| タイトル | A RANKL-derived Peptide Inhibits RSPO3-LGR4-Wnt Signaling and Lung Adenocarcinoma in Mice. |
| ジャーナル | Anticancer Res |
| Abstract |
BACKGROUND/AIM:Despite advances in therapy, lung cancer remains the leading cause of cancer-related mortality. R-spondin (RSPO) 3 and its receptor, leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), drive tumor progression in a subset of lung adenocarcinomas by potentiating Wnt signaling. In addition to RSPO3, LGR4 is also a receptor for receptor activator of nuclear factor-кB ligand (RANKL). Here, we investigated whether MHP1-AcN, our previously developed RANKL-derived peptide, acts on LGR4 and examined its effects on RSPO3-LGR4 signaling in A549 lung cancer cells. MATERIALS AND METHODS:An A549 xenograft model was established by subcutaneous inoculation in BALB/c nude mice, followed by daily intraperitoneal administration of MHP1-AcN. Tumor growth was assessed by volume and weight. In vitro, the effect of MHP1-AcN on A549 cell proliferation, cytotoxicity, migration, and invasion were evaluated. Molecular interactions and signaling pathways were analyzed using immunoprecipitation and immunoblotting. RESULTS:Intraperitoneal administration of MHP1-AcN significantly reduced tumor volume and weight in the subcutaneous A549 xenograft model. Mechanistically, MHP1-AcN directly interacted with LGR4 and disrupted RSPO3-induced LGR4-IQ motif-containing GTPase activating protein 1 complex formation. MHP1-AcN inhibited A549 cell proliferation without inducing cytotoxicity and suppressed RSPO3-enhaced phosphorylation of LRP6 and accumulation of β-catenin. Furthermore, MHP1-AcN dose-dependently inhibited A549 cell migration and invasion by reducing focal adhesion kinase phosphorylation and disrupting F-actin organization. CONCLUSION:These findings demonstrate MHP1-AcN as a novel LGR4 antagonist that inhibits RSPO3-LGR4-Wnt signaling, tumor growth, and metastatic potential in lung adenocarcinoma, highlighting its potential as a therapeutic agent targeting this pathway. |
| 巻・号 | 46(6) |
| ページ | 3033-3045 |
| 公開日 | 2026-6-1 |
| DOI | 10.21873/anticanres.18178 |
| PII | 46/6/3033 |
| PMID | 42203310 |
| MeSH | A549 Cells Adenocarcinoma of Lung* / drug therapy Adenocarcinoma of Lung* / metabolism Adenocarcinoma of Lung* / pathology Animals Cell Movement / drug effects Cell Proliferation / drug effects Humans Lung Neoplasms* / drug therapy Lung Neoplasms* / metabolism Lung Neoplasms* / pathology Male Mice Mice, Inbred BALB C Mice, Nude Peptides* / pharmacology R-Spondins RANK Ligand* / chemistry RANK Ligand* / pharmacology Receptors, G-Protein-Coupled* / metabolism Thrombospondins* / metabolism Wnt Signaling Pathway* / drug effects Xenograft Model Antitumor Assays |
| IF | 1.994 |
| リソース情報 | |
| ヒト・動物細胞 | A549(RCB0098) |