RLIP depletion suppresses ovarian cancer growth and metastasis

Ovarian tumor metastasis is a leading cause of cancer-related deaths worldwide. Ovarian cancer (OC) cells frequently metastasize to the peritoneum. OC cells, after detaching from the primary tumor, can float in the ascitic fluid (fluid that accumulates in the abdominal cavity due to cancer) and attach to the peritoneum, the lining of the abdominal cavity. Peritoneal metastasis is strongly linked to poor prognosis in OC patients. In the current study, we evaluated the anti-proliferative and anti-metastatic effects of RLIP inhibition in an array of OC cell lines and an orthotopic mouse model of ovarian metastasis. Compared to control treatment, RLIP inhibition and/or depletion reduced in-vitro cell viability and suppressed the migratory and invasive potential of OC cells. Further, mice intraperitoneally implanted with luciferase-expressing HeyA8 OC cells were treated with RLIP antisense (RAS; 4 mg/kg, b.w.), RLIP antibody (Rab; 4 mg/kg, b.w.) or a combination of RAS+Rab. RAS-, and Rab-treated mice exhibited significantly lower primary tumor weight and reduced metastasis compared to control mice. Mice treated with a combination of RAS+Rab exhibited no metastasis and significantly lower tumor weight than the single agent-treated mice. In-vivo studies showed that the RLIP targeting agent's treatment prolonged the survival of NSG mice inoculated with HeyA8-luc OC cells. Collectively, our results suggest that RLIP antisense has potential to be combined with RLIP antibodies to more effectively suppress primary ovarian tumor growth and metastasis to the peritoneum that warrants further investigation. (This work was supported in part by the Department of Defense grant W81XWH-22-1-0331. Funding from the Beckman Research Institute of City of Hope is also acknowledged).