Abstract 5422: Inhibition of oxidosqualene cyclase blocks proliferation and survival of prostate cancer cells

Abstract

Abstract Despite concerted efforts to develop new strategies for preventing and treating prostate cancer, almost 240,000 new cases of the disease are reported each year in the United States, and more than 28,000 men die of the disease annually. Most deaths occur due to complications following metastasis from the primary prostate tumor to other tissues and organs, a process dependent upon increased angiogenesis. Human prostate cancer cells are often dependent on endogenous or exogenous androgens and estrogens, which stimulate cell proliferation and metastasis and inhibit cell death. Standard treatment for primary prostate cancer often includes systemic exposure to chemotherapeutic drugs or antihormones (chemical castration); however, drug-resistant cancer cells often emerge during treatment, limiting the continued use of systemic chemotherapy. Therefore, novel, less toxic and more effective treatments for prostate cancer are urgently needed. The cholesterol biosynthetic pathway is an attractive therapeutic target for endocrine dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as being the metabolic precursor of endogenous steroid hormones. Due to certain undesirable side-effects associated with statins, such as reduced levels of isoprenoids, defective post-translational modification of membrane proteins, and impaired membrane structure and function, alternative approaches are under consideration. 2, 3-oxidosqualene cyclase (OSC) is a key enzyme in the cholesterol biosynthetic pathway downstream of HMGCoA-reductase, the target of statins. While studying anti-cancer properties of Ro 48-8071 [4′-[6-(Allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate]) (RO), an OSC inhibitor, we found that as well as reducing tumor cell viability, RO simultaneously induced the anti-proliferative protein estrogen receptor β (ERβ). Moreover, RO also elevated ERβ in hormone-insensitive cells that are difficult to treat clinically. Initial studies suggest that combining RO with an ERβ agonist increases the antiproliferative effects of RO in prostate cancer cells. RO also induced apoptosis in prostate cancer cells, determined by FACS analysis. In addition, RO effectively reduced the growth of prostate cancer xenografts (PC3 cells) in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells (RWPE-1). Our study is the first to demonstrate that disrupting cholesterol biosynthesis through OSC inhibition is a novel and potent means by which to destroy human prostate cancer cells. Further studies are necessary to determine the mechanism of RO-mediated loss of prostate cancer cell viability. Support: Department of Defense Prostate Cancer Pgm grant W81XWH-14-1-0246, NIH grant R21 GM088517, and by a COR grant from the University of Missouri, Columbia. Note: This abstract was not presented at the meeting. Citation Format: Yayun Liang, Benford Mafuvadze, Xiaoqin Zou, Cynthia Besch-Williford, Salman M. Hyder. Inhibition of oxidosqualene cyclase blocks proliferation and survival of prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2015-5422