Elucidating the Role of Translocator Protein in Prostate Cancer

摘要

Purpose: To determine the functional role of Translocator Protein (TSPO) in prostate cancer progression. Scope: To demonstrate the effect of TSPO ligands in prostate cancer, we utilized cell proliferation assays, apoptosis ELISAs, and a prostate cancer mouse xenograft study. Our findings provide the first evidence of the anti-tumor effects of lorazepam acting on TSPO. To determine the effect of modulating TSPO expression, we performed overexpression and knockdown studies. These studies provided further evidence that lorazepam is acting through TSPO, as overexpression of TSPO conferred increased susceptibility to lorazepam while TSPO knockdown decreased susceptibility. We investigated the role of TSPO multimers in prostate cancer. TSPO multimers can be induced by reactive oxygen species and may be formed through a di-tyrosine covalent bond. TSPO expression increases with prostate cancer progression. The benzodiazepine lorazepam exerts its anticancer effects through its binding to TSPO. Major findings: Collectively, these data suggest that TSPO is an excellent therapeutic target for advanced disease and that our preclinical results demonstrating that the already existing FDA-approved drug lorazepam has anti-tumor effects could be easily translated to the prostate cancer patient population. These studies could lead to a significant change in the management of prostate cancer by providing a treatment option with minimal toxicity for use in advanced disease and could ultimately prevent prostate cancer deaths.