Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells

Abstract

Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a resistance mechanism to PSMA-based imaging and therapy. Clinical studies revealed that androgen receptor (AR) inhibition increases PSMA expression. The mechanism has not yet been elucidated. Therefore, this study investigated the effect of activation and inhibition of androgen signaling on PSMA expression levels in vitro and compared these findings with PSMA levels in PCa patients receiving systemic therapy. To this end, LAPC4, LNCaP, and C4-2 PCa cells were treated with various concentrations of the synthetic androgen R1881 and antiandrogens. Changes in FOLH1 mRNA were determined using qPCR. Open access databases were used for ChIP-Seq and tissue expression analysis. Changes in PSMA protein were determined using western blot. For PSMA staining in patients’ specimens, immunohistochemistry (IHC) was performed. Results revealed that treatment with the synthetic androgen R1881 led to decreased FOLH1 mRNA and PSMA protein. This effect was partially reversed by antiandrogen treatment. However, AR ChIP-Seq analysis revealed no canonical AR binding sites in the regulatory elements of the FOLH1 gene. IHC analysis indicated that androgen deprivation only resulted in increased PSMA expression in patients with low PSMA levels. The data demonstrate that AR activation and inhibition affects PSMA protein levels via a possible non-canonical mechanism. Moreover, analysis of PCa tissue reveals that low PSMA expression rates may be mandatory to increase PSMA by androgen deprivation.

Reinforcement of the Tumor Suppressing Properties of microRNA-1 by Substitution at the C2′ Position of Varying Ribose Residues in Chemically Synthesized microRNA-1 Molecules

“…Presumably due to wellknown cellular and molecular differences between both cell lines, e.g. in androgen sensitivity, androgen receptor expression, and p53 status (48,49), PC-3 cells are more resistant to anticancer treatment than LNCaP cells, as suggested by literature data (50)(51)(52)(53). Additionally, one cannot exclude the possibility of varying transfection efficiencies utilizing chemically modified RNA molecules for the transfection of LNCaP and PC-3 cells.…”

Discrepancy between Biochemical and Radiological Response in Metastatic Hormone- Sensitive Prostate Cancer: A Case Report and Literature Review

“…The expression of PSMA can be very heterogeneous [22][23][24]. Many in vitro and in vivo studies showed that PSMA expression and PSA secretion are independently regulated with different behaviour after treatment with anti-hormones [25,26]. It seems that in men with hormonesensitive cancers, androgen deprivation leads in most cases to a decrease in maximum and mean standardized uptake value (SUV) at PSMA PET/CT as well as PSA secretion.…”

Influence of Androgen Deprivation Therapy on the PD-L1 Expression and Immune Activity in Prostate Cancer Tissue

“…The patient’s cohort has previously been described in Sommer et al, 2022 and the samples were selected from the Tumor and Normal Tissue Bank of the University Cancer Center Dresden ( Ebersbach et al, 2022 ; Sommer et al, 2022 ). The cohort of this study contained 116 tissue specimens of 97 PCa patients undergoing transurethral resection of the prostate (TURP) recruited from 2011 to 2020.…”