Adipokine apelin/APJ pathway promotes peritoneal dissemination of ovarian cancer cells by regulating lipid metabolism

Adipose tissue, which can provide adipokines and nutrients to tumors, plays a key role in promoting ovarian cancer metastatic lesions in peritoneal cavity. The adipokine apelin promotes ovarian cancer metastasis and progression through its receptor APJ, which regulates cell proliferation, energy metabolism, and angiogenesis. The objective of this study was to investigate the functional role and mechanisms of the apelin-APJ pathway in ovarian cancer metastasis, especially in context of tumor cell-adipocyte interactions. When co-cultured in the conditioned media (AdipoCM) derived from 3T3-L1 adipocytes, which express and secrete high apelin, human ovarian cancer cells with high APJ expression showed significant increases in migration and invasion in vitro. We also found that cells expressing high levels of APJ had increased cell adhesion to omentum ex vivo, and preferentially "home-in"on the omentum in vivo. These apelin-induced pro-metastatic effects were reversed by APJ antagonist F13A in a dose-dependent manner. Apelin-APJ activation increased lipid droplet accumulation in ovarian cancer cells, which was further intensified in the presence of AdipoCM and reversed by F13A or APJ knockdown. Mechanistically, this increased lipid uptake was mediated by CD36 upregulation via APJ-STAT3 activation, and the lipids were utilized in promoting fatty acid oxidation via activation of AMPK-CPT1a axis. Together, our studies demonstrate that adipocyte-derived apelin activates APJ-expressing tumor cells in a paracrine manner, promoting lipid uptake and utilization and providing energy for ovarian cancer cell survival at the metastatic sites. Hence, the apelin- APJ pathway presents a novel therapeutic target to curb ovarian cancer metastasis. Implications: Targeting the APJ pathway in high-grade serous ovarian carcinoma is a novel strategy to inhibit peritoneal metastasis.