Cancer Therapy : Preclinical Translocator Protein Blockade Reduces Prostate Tumor Growth

Purpose: The transmembrane molecule, translocator protein (TSPO), has been implicated in the progression of epithelial tumors. TSPO gene expression is high in tissues involved in steroid biosynthesis, neurodegenerative disease, and in cancer, and overexpression has been shown to contribute to pathologic conditions including cancer progression in several different models. The goal of our study was to examine the expression and biological relevance of TSPO in prostate cancer and show that the commonly prescribed benzodiazepine lorazepam, a ligand for TSPO, exhibits anticancer properties. Experimental Design: Immunohistochemical analysis using tissue microarrays was used to determine the expression profile of TSPO in human prostate cancer tissues. To show the effect of TSPO ligands (lorazepam and PK11195) in prostate cancer, we used cell proliferation assays, apoptosis ELISA, prostate cancer xenograft study, and immunohistochemistry. Results: TSPO expression is increased in prostatic intraepithelial neoplasia, primary prostate cancer, and metastases compared with normal prostate tissue and benign prostatic hyperplasia. Furthermore, TSPO expression correlates with disease progression, as TSPO levels increased with increasing Gleason sum and stage with prostate cancer metastases demonstrating the highest level of expression among all tissues examined. Functionally, we have shown that lorazepam has antiproliferative and proapoptotic properties in vitro and in vivo. Additionally, we have shown that TSPO overexpression in nontumorigenic cells conferred susceptibility to lorazepam-induced growth inhibition. Conclusion: These data suggest that blocking TSPO function in tumor cells induces cell death and denotes a survival role for TSPO in prostate cancer and provides the first evidence for the use of benzodiazepines in prostate cancer therapeutics. (Clin Cancer Res 2009;15(19):6177–84) Translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is a transmembrane molecule that is best known for transporting cholesterol across the mitochondrial membrane for cell signaling and steroid biosynthesis (1, 2). TSPO has been shown to be overexpressed in numerous malignancies, including those of the breast, prostate, colon, ovary, and endometrium (3–7). Furthermore, a correlation has been shown between TSPO overexpression and the progression of breast, colorectal, and prostate cancers (8). Functionally, TSPO has been shown to take part in the regulation of apoptosis through its interactions with the mitochondrial permeability transition pore (9, 10). TSPO also plays a role in cell proliferation, as a correlation between TSPO expression and cancer cell proliferation has been observed in human astrocytomas (11) and breast cancer (12), whereas TSPO antagonism inhibits cell proliferation (13–16). As its former name suggests, the peripheral-type benzodiazepine receptor, now called TSPO, has the ability to bind benzodiazepines with relatively high affinity (17). Benzodiazepine receptors are found in both the central and peripheral nervous Authors' Affiliations: Departments of Urology and Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, Department of Urology, Mount Sinai Hospital, New York, New York, and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania Received 4/3/09; revised 6/18/09; accepted 7/2/09; published OnlineFirst 9/29/09. Grant support: National Center for Research Resources (NCRR, a component of the NIH) grant no. 5 UL1 RR024153 and NIH Roadmap for Medical Research (B. Pflug and A. Parwani), and by Department of Defense Predoctoral grant PC080062 (A. Fafalios). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR, the NIH, or the Department of Defense. Information on the NCRR is available at http://www.ncrr.nih.gov/. Information on Reengineering the Clinical Research Enterprise can be obtained from http:// nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Beth R. Pflug, Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, Myers Bldg. W7801E, 1001 West 10th St., Indianapolis, IN 46202. Phone: 317-630-8676. E-mail: bpflug@iupui.edu. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0844 6177 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Research. on May 3, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 29, 2009; DOI: 10.1158/1078-0432.CCR-09-0844