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Published on: March 6, 2018
Translocator protein blockade reduces prostate tumor growth
Arlee Fafalios1, Ardavan Akhavan, Anil V Parwani
1Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
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.
Insights
Translocator protein (TSPO) is upregulated in prostate cancer, promoting tumor growth. The drug lorazepam, a TSPO ligand, demonstrated anticancer effects by inhibiting proliferation and inducing cell death in prostate cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Transmembrane protein TSPO is implicated in epithelial tumor progression.
- TSPO gene expression is elevated in steroid biosynthesis, neurodegenerative diseases, and cancers.
- Overexpression of TSPO contributes to pathological conditions, including cancer progression.
Purpose of the Study:
- To investigate TSPO expression and biological significance in prostate cancer.
- To evaluate the anticancer potential of lorazepam, a TSPO ligand, in prostate cancer.
Main Methods:
- Immunohistochemical analysis of TSPO expression in human prostate cancer tissues using tissue microarrays.
- In vitro and in vivo studies utilizing cell proliferation assays, apoptosis ELISA, and xenograft models.
- Assessment of TSPO ligand effects (lorazepam, PK11195) on prostate cancer cells.
Main Results:
- TSPO expression is significantly increased in prostatic intraepithelial neoplasia, primary prostate cancer, and metastases compared to normal or benign tissues.
- TSPO levels correlate with prostate cancer progression, including Gleason sum and stage, with highest expression in metastases.
- Lorazepam exhibits significant antiproliferative and proapoptotic effects in vitro and in vivo, particularly in cells overexpressing TSPO.
Conclusions:
- TSPO plays a survival role in prostate cancer, and its inhibition induces tumor cell death.
- Blocking TSPO function represents a potential therapeutic strategy for prostate cancer.
- Benzodiazepines, such as lorazepam, show promise as novel therapeutic agents for prostate cancer.
