A multi‐parameter imaging assay identifies different stages of ligand‐induced androgen receptor activation

Royen, Martin E. van; Wijngaart, Dennis J. van de; Cunha, Sónia; Trapman, Jan; Houtsmuller, Adriaan B.

doi:10.1002/cyto.a.22284

Cited by 9 publications

(9 citation statements)

References 78 publications

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“…The block of the N/C-terminal interaction by known antagonists is strongly associated with an inhibition of DNA binding and transcriptional activity of the receptor (20). This is in line with our observations using FRAP assays that indicate a reduced immobilization and a higher mobility of the AR in the presence of AA-bound AR compared with androgens.…”

Section: Discussionsupporting

confidence: 88%

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A Natural Androgen Receptor Antagonist Induces Cellular Senescence in Prostate Cancer Cells

Hessenkemper

Roediger

Bartsch

et al. 2014

Molecular Endocrinology

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We have previously identified a natural occurring, androgen receptor-specific antagonist. Atraric acid (AA) inhibits the transactivation of the androgen receptor (AR) and androgen-mediated growth of AR-expressing human prostate cancer (PCa) cell lines. Here we show that AA treatment of living cells provokes molecular changes of AR signaling. In addition to a deceleration of nuclear translocation a block of the intramolecular amino/carboxy (N/C)-terminal interaction of the AR was observed. Furthermore, using high-resolution confocal fluorescence microscopy, a reduced speckle formation of the AR was observed in line with an increased intranuclear mobility of the receptor. This suggests decreased DNA binding of the AR, which is further indicated by an impaired chromatin recruitment of the AR to the prostate-specific antigen promoter and enhancer shown by chromatin immunoprecipitation experiments. Using inhibitors of the non-receptor tyrosine kinase Src or Akt, known interaction partners of AR, reduced the level of androgen-induced cellular senescence suggesting a partly non-genomic pathway to induce cellular senescence by AA. Using PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) pyrimidine or Akt inhibitors, inhibitors of the nonreceptor tyrosine kinase Src or Akt, known interaction partners of AR, reduced the level of androgen-induced cellular senescence, suggesting a partly nongenomic pathway to induce cellular senescence by AA. Treatment of LNCaP cells with AA is associated with hypophosphorylation of the retinoblastoma tumor suppressor and an increase of p16 expression, whereas the p53-p21 signaling pathway seems not be affected by AA treatment. Analyzing human PCa tissue samples treated with AA ex vivo also indicates an induction of cellular senescence associated with an increase of p16 expression but not p21. Taken together, these data indicate that AA exhibits novel features to inhibit AR amino/carboxy-terminal interaction, the AR-mediated nuclear activities and growth of PCa cells.

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Section: Discussionsupporting

confidence: 88%

“…A strong correlation between the agonist-induced AR N/C-terminal interaction, DNA binding, and full transcriptional activity of the receptor has been described (20). Therefore, the effect on both the AR N/Cterminal interaction and intranuclear mobility were investigated.…”

Section: Aa Prevents Ar N/c-terminal Interaction and Reduces The Agonmentioning

confidence: 99%

A Natural Androgen Receptor Antagonist Induces Cellular Senescence in Prostate Cancer Cells

Hessenkemper

Roediger

Bartsch

et al. 2014

Molecular Endocrinology

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“…Within the nucleus, GFP-AR showed a striking transition from no detectable correlation before Cl-4AS-1 treatment, suggesting the majority of GFP-AR to be diffusive, to long, consistent correlation after adding ligand. This AR agonist-induced binding in the nucleus has been reported previously in other studies 19 20 37 . Within the cytoplasm, GFP-AR showed the decreased diffusion after Cl-4AS-1 treatment.…”

Section: Resultssupporting

confidence: 89%

Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS)

Chiu

Patsch²,

Cutrale

et al. 2016

Sci Rep

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The androgen receptor (AR) pathway plays a central role in prostate cancer (PCa) growth and progression and is a validated therapeutic target. In response to ligand binding AR translocates to the nucleus, though the molecular mechanism is not well understood. We therefore developed multimodal Image Correlation Spectroscopy (mICS) to measure anisotropic molecular motion across a live cell. We applied mICS to AR translocation dynamics to reveal its multimodal motion. By integrating fluorescence imaging methods we observed evidence for diffusion, confined movement, and binding of AR within both the cytoplasm and nucleus of PCa cells. Our findings suggest that in presence of cytoplasmic diffusion, the probability of AR crossing the nuclear membrane is an important factor in determining the AR distribution between cytoplasm and the nucleus, independent of functional microtubule transport. These findings may have implications for the future design of novel therapeutics targeting the AR pathway in PCa.

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“…If such errors are repairable, the cell amends such errors via molecular control mechanisms by literarily stitching the broken DNA material into the rest of the genome. Although the cell is equipped with the metabolic machinery to stitch the broken genetic fragments during replication, it is however not endowed with tools to recognize the actual sites [15][16][17][18][19][20]. In certain circumstances, the fragmented gene is stitched to a wrong site which might alter gene regulatory region that will prone a cell to over expression of certain proteins that can lead to excessive transcription of genes (cancers) -if the gene regulatory region is altered.…”

Section: Resultsmentioning

confidence: 99%

“…Certain invasive cancer cells also showed CathD over expression in isolated cell populations within the glandular tissue (Figure 4 PCa). Kedia and co-workers [18,19] have reportedly observed CathD expression in the surface and cytoplasm of tumor cells invading glandular tissue and in single cells involving prostatic stoma. This is equally important in the determination of biological aggressiveness of prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

Roles of Cell Cycle Regulators [p53, Cathepsin-D and Bax] in Prognostic Determination of Prostate Cancer and Benign Prostatic Hyperplasia

Olalekan¹,

Ajonijebu²,

Tolulope³

et al. 2013

J Carcinog Mutagen

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Background:The prostate gland is an almond-shaped gland located directly below the urinary bladder and circling the prostatic urethra. The incidence of prostatic disorders has been found to increase with age; especially in PCa and BPH. PCa and BPH are both characterized by cell proliferation and active division at specific tissue sites. The two forms of cell proliferation are regulated by cell cycle and are perhaps created by molecular mechanisms dysregulation that will alter such regulatory mechanisms.Method: Human prostate biopsies were obtained from clinically diagnosed patients and were studied immunohistochemically to map the distribution of p53, CathD and Bax. Results and conclusion:In PCa, the increased levels of p53 and Bax signals pre-apoptotic tendencies for rapidly proliferating un-coordinated cells which can be located at random locations due to loss of matrix and adhesion molecules described in high CathD levels. Co-localization of p53, CathD and Bax can be insightful to further determine the role cell cycle in BPH and PCa and in distinguishing the patterns of cell proliferation in both conditions.

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A multi‐parameter imaging assay identifies different stages of ligand‐induced androgen receptor activation

Cited by 9 publications

References 78 publications

A Natural Androgen Receptor Antagonist Induces Cellular Senescence in Prostate Cancer Cells

A Natural Androgen Receptor Antagonist Induces Cellular Senescence in Prostate Cancer Cells

Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS)

Roles of Cell Cycle Regulators [p53, Cathepsin-D and Bax] in Prognostic Determination of Prostate Cancer and Benign Prostatic Hyperplasia

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