The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells
Journal
Prostate
Journal Volume
72
Journal Issue
7
Pages
803-816
Date Issued
2012
Author(s)
Abstract
Background Androgen receptor (AR) is the main therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy (ADT) is only effective for a short period of time. Here we tested PTS33, a new sodium derivative of cryptotanshinone, which can effectively inhibit the DHT-induced AR transactivation and PCa cell growth, and then explored the effects of PTS33 on inhibiting the expressions of AR target genes and proteins. Methods PCa cells, LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with PTS33 and luciferase assay was used to evaluate the ability of each to regulate AR transactivation. RT-PCR was used to evaluate the mRNA levels of AR target genes such as PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR, PSA, estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and progesterone receptor (PR) protein expression. Cell growth and IC 50 were determined by MTT assay after 48 hr treatment. Results Our data showed that PTS33 selectively inhibits AR activities, but PTS33 does not repress the activities of other nuclear receptors, including ERα, GR, and PR. At a low concentration, 2 μM of PTS33 effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Furthermore, our data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 can also inhibit estrogen/Δ5-androstenediol induced AR activities. The mechanistic studies indicate that PTS33 can inhibit AR function by suppression of AR protein expression, the AR N-C interaction, and AR-coregulator interaction. Conclusions PTS33 has shown a good efficacy to inhibit AR transactivation, block AR regulated gene expression, and reduce cell growth in AR positive PCa cells. The structure of PTS33 could be used as a base for development of novel AR signaling inhibitors to treat PCa. ? 2011 Wiley Periodicals, Inc.
Subjects
androgen receptor; anti-androgen; Danshen; prostate cancer; tanshinone
SDGs
Other Subjects
androgen receptor; androstanolone; antineoplastic agent; cryptotanshinone; estrogen receptor alpha; glucocorticoid receptor; luciferase; messenger RNA; progesterone receptor; prostate specific antigen; protein; pts 33; transmembrane prostate androgen induced protein a1; transmembrane protease serine 2; unclassified drug; cancer cell culture; castration resistant prostate cancer; enzyme assay; gene repression; human; human cell; IC 50; male; priority journal; prostate cancer; protein expression; regulatory mechanism; reverse transcription polymerase chain reaction; review; transactivation; tumor growth; Western blotting; Adenocarcinoma; Cell Line, Tumor; Estrogen Receptor alpha; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Proteins; Phenanthrenes; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Receptors, Glucocorticoid; Receptors, Progesterone; Serine Endopeptidases
Type
review