Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter

• Published in: Carcinogenesis (New York) 2024-09, Vol.45 (9), p.696-707
• Main Authors: Krishna, B Madhu, Ramisetty, Sravani K, Garg, Pankaj, Mohanty, Atish, Wang, Edward, Horne, David, Awasthi, Sanjay, Kulkarni, Prakash, Salgia, Ravi, Singhal, Sharad S
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP-Binding Cassette Transporters; Carboplatin - pharmacology; Cell Line, Tumor; Female; GTPase-Activating Proteins; Humans; Mice; Mice, Nude; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgae047

Abstract Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione–electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment. We demonstrate the indispensable role of RLIP in the development of ovarian cancer, observing a significantly elevated expression in ovarian cancer cells compared with nonmalignant cells. Depletion or inhibition of RLIP effectively hinders the processes of ovarian carcinogenesis and metastasis. Graphical Abstract Graphical Abstract