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Small Molecule Targeting of Oxysterol-Binding Protein (OSBP)-Related Protein 4 and OSBP Inhibits Ovarian Cancer Cell Proliferation in Monolayer and Spheroid Cell Models
journal contribution
posted on 2021-02-04, 20:03 authored by Ryan C. Bensen, Gokhan Gunay, Matthew C. Finneran, Isha Jhingan, Handan Acar, Anthony W. G. BurgettThe
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.