Temporal and Spatial Dynamics of Androgen Receptor Conformation and Interactions in Prostate Cancer Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

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SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

Scientific Reports ◽

10.1038/s41598-021-93971-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Diana Trnski ◽

Maja Sabol ◽

Sanja Tomić ◽

Ivan Štefanac ◽

Milanka Mrčela ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Therapy Resistance ◽

Androgen Deprivation ◽

Prostate Cancer Cells ◽

Androgen Independence ◽

Androgen Receptor Activity ◽

Signaling Activation ◽

Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

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White Button Mushroom (Agaricus bisporus) Disrupts Androgen Receptor Signaling in Human Prostate Cancer Cells and Patient-Derived Xenograft

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2020.108580 ◽

2020 ◽

pp. 108580

Author(s):

Xiaoqiang WANG ◽

Desiree Ha ◽

Hitomi Mori ◽

Shiuan Chen

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Agaricus Bisporus ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Button Mushroom ◽

Androgen Receptor Signaling ◽

Patient Derived Xenograft

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Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.055 ◽

2011 ◽

Vol 5 (1) ◽

Author(s):

Harri Makkonen ◽

Jorma J. Palvimo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Binding Sites ◽

Target Genes ◽

Three Dimensional ◽

Regulatory Elements ◽

Gene Promoters ◽

Loop Formation ◽

Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

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