Abstract
Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion.
Highlights
Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein overexpressed in prostate carcinoma
Reports have shown PSMA is up-regulated by androgen ablation [12]; we found that the response of PSMA to androgen treatment was different in VCaP and LNCaP prostate cancer cell lines
We found PSMA was downregulated by TMPRSS2-ERG fusion in VCaP prostate cancer cells
Summary
Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein overexpressed in prostate carcinoma. PSMA can undergo internalization, and its intracellular domain is known to bind to actin binding protein filamin A [2,3]. Most prostate cancer cells express PSMA, and its expression has been correlated with aggressive disease [4,5,6]. In addition to normal prostate gland, benign prostatic hyperplasia (BPH), and prostate cancer (PCa), PSMA is expressed in the neovasculature of multiple solid tumors [7,8,9,10]. Higher PSMA expression is found in cancer cells from castration-resistant prostate cancer patients. Increased PSMA expression is reported to correlate with the risk of early prostate cancer recurrence after radical prostatectomy [5,11,12]. Investigating the mechanism of PSMA regulation will allow us to better understand the mechanisms and functions of PSMA in prostate cancer
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
