Targeting the oncoprotein RLIP as novel therapy for ovarian cancer.

Ral-interacting/binding protein (RLIP/RalBP1) is a multifunctional protein found in the plasma membrane, cytosol, and nucleus, with broad expression across various tissues, including the ovary. In tumorigenesis, RLIP is closely linked to the progression of solid tumors. As a non-ABC anti-apoptotic transporter, it facilitates glutathione (GSH) conjugate transport, which plays a role in receptor-ligand endocytosis and contributes to drug transport and resistance. Its overexpression in multiple malignant cell lines suggests a critical role in cancer cell survival. In ovarian cancer (OC) cell lines, reducing or suppressing RLIP levels whether through antibodies or antisense approaches induces apoptosis, even in the absence of chemotherapy. When combined with carboplatin, RLIP depletion significantly enhances cell death in both in vitro and in vivo models, suggesting that RLIP downregulation promotes apoptosis through both drug-dependent and independent mechanisms. To evaluate the impact of RLIP-specific depletion on apoptosis, we applied RLIP antisense across different OC cell lines and consistently observed growth inhibition and cell death. Further, the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin was confirmed in cell cultures and OVCAR8 OC cell xenografts. Notably, RLIP inhibition via antibodies was as effective as antisense in enhancing carboplatin’s efficacy in OC xenografts. These findings underscore RLIP as a promising therapeutic target for OC treatment.