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Mol Cancer Res. 2019 Jun;17(6):1378-1390. doi: 10.1158/1541-7786.MCR-18-0989. Epub 2019 Mar 11.

Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
2
Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
3
Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
4
Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
5
Department of Pathology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
6
Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
7
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. sukyung-woo@ouhsc.edu.
#
Contributed equally

Abstract

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 in vitro, 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 in vivo. 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.

PMID:
30858172
PMCID:
PMC6548659
[Available on 2020-06-01]
DOI:
10.1158/1541-7786.MCR-18-0989

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