Small Molecule Targeting of Oxysterol-Binding Protein (OSBP)-Related Protein 4 and OSBP Inhibits Ovarian Cancer Cell Proliferation in Monolayer and Spheroid Cell Models.

Abstract

The development of precision drugs for the selective treatment of ovarian cancer will require targeting proliferative factors selectively expressed in ovarian tumors or targeting unique physiological microenvironments specific for ovarian tumors. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 (ORP4) is a potential druggable precision target in ovarian cancer cells. ORP4 has limited expression in normal tissues and was recently recognized to be a cancer-specific driver of cellular proliferation, including in patient-isolated leukemias. We demonstrate that ORP4 is strongly expressed in a panel of ovarian cancer cell lines. The antiproliferative natural product compound OSW-1 targets ORP4 and OSBP. Our results demonstrate that the OSW-1 compound has high antiproliferative potency in both monolayer and three-dimensional ovarian cancer spheroid models, especially compared to the standard-of-care agents cisplatin and paclitaxel. OSW-1 compound treatment induces a loss of ORP4 expression after 48 h, which is coincident with the cytotoxic effects of OSW-1. The absence of extracellular lipids markedly potentiated the cytotoxicity of OSW-1, which was reversed by addition of extracellular free cholesterol. OSBP, but not ORP4, is reported to transport cholesterol and other lipids between organelles. Our results indicate that the targeting of ORP4 is responsible for the antiproliferative activity of the OSW-1 compound, but that in the absence of exogenously supplied cholesterol, which might be similar to the in vivo ovarian cancer microenvironment, possible OSW-1 targeting of OSBP further potentiates the anticancer activity of the compound. Overall, ORP4 and potentially OSBP are revealed as potential druggable targets for the development of novel treatments for ovarian cancer.