Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis

• Published in: Molecular cancer research 2019-06, Vol.17 (6), p.1378-1390
• Main Authors: Neelakantan, Deepika, Dogra, Samrita, Devapatla, Bharat, Jaiprasart, Pharavee, Mukashyaka, Marie Claire, Janknecht, Ralf, Dwivedi, Shailendra Kumar Dhar, Bhattacharya, Resham, Husain, Sanam, Ding, Kai, Woo, Sukyung
• Format: Article
• Language: English
• Subjects: Animals; Apelin Receptors - metabolism; Cell Adhesion - physiology; Cell Line; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation - physiology; Disease Progression; Extracellular Matrix - metabolism; Female; Humans; MAP Kinase Signaling System - physiology; Mice; Mice, Nude; Neoplasm Metastasis - pathology; Nitrobenzoates - pharmacology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Pyrans - pharmacology; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0989

High mortality rates in ovarian cancer are due to late-stage diagnosis when extensive metastases are present, coupled with the eventual development of resistance to standard chemotherapy. There is, thus, an urgent need to identify targetable pathways to curtail this deadly disease. In this study, we show that the apelin receptor, APJ, is a viable target that promotes tumor progression of high-grade serous ovarian cancer (HGSOC). APJ is specifically overexpressed in tumor tissue, and is elevated in metastatic tissues compared with primary tumors. Importantly, increased APJ expression significantly correlates with decreased median overall survival (OS) by 14.7 months in patients with HGSOC. Using various ovarian cancer model systems, we demonstrate that APJ expression in cancer cells is both necessary and sufficient to increase prometastatic phenotypes , including proliferation, cell adhesion to various molecules of the extracellular matrix (ECM), anoikis resistance, migration, and invasion; and these phenotypes are efficiently inhibited by the APJ inhibitor, ML221. Overexpression of APJ also increases metastasis of ovarian cancer cells . Mechanistically, the prometastatic STAT3 pathway is activated downstream of APJ, and in addition to the ERK and AKT pathways, contributes to its aggressive phenotypes. Our findings suggest that the APJ pathway is a novel and viable target, with potential to curb ovarian cancer progression and metastasis. IMPLICATIONS: The APJ pathway is a viable target in HGSOC.