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ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin
- Source :
- Cell cycle (Georgetown, Tex.). 15(3)
- Publication Year :
- 2015
-
Abstract
- The realization, that the androgen receptor (AR) is essential for prostate cancer (PC) even after relapse following androgen deprivation therapy motivated the search for novel types of AR inhibitors. We proposed that targeting AR expression versus its function would work in cells having either wild type or mutant AR as well as be independent of androgen synthesis pathways. Previously, using a phenotypic screen in androgen-independent PC cells we identified a small molecule inhibitor of AR, ARTIK-52. Treatment with ARTIK-52 caused the loss of AR protein and death of AR-positive, but not AR-negative, PC cells. Here we present data that ARTIK-52 induces degradation of AR mRNA through a mechanism that we were unable to establish. However, we found that ARTIK-52 is toxic to breast cancer (BC) cells expressing AR, although they were not sensitive to AR knockdown, suggesting an AR-independent mechanism of toxicity. Using different approaches we detected that ARTIK-52 induces replication-dependent double strand DNA breaks exclusively in cancer cells of prostate and breast origin, while not causing DNA damage, or any toxicity, in normal cells, as well as in non-PC and non-BC tumor cells, independent of their proliferation status. This amazing specificity, combined with such a basic mechanism of toxicity, makes ARTIK-52 a potentially useful tool to discover novel attractive targets for the treatment of BC and PC. Thus, phenotypic screening allowed us to identify a compound, whose properties cannot be predicted based on existing knowledge and moreover, uncover a barely known link between AR and DNA damage response in PC and BC epithelial cells.
- Subjects :
- 0301 basic medicine
DNA Replication
Male
DNA damage
Phenotypic screening
Carbazoles
Breast Neoplasms
Biology
Real-Time Polymerase Chain Reaction
Androgen deprivation therapy
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell Line, Tumor
Report
medicine
Androgen Receptor Antagonists
Humans
RNA, Messenger
RNA, Small Interfering
Molecular Biology
Gene knockdown
Prostate
Prostatic Neoplasms
Cell Biology
medicine.disease
Blotting, Northern
Molecular biology
Androgen receptor
030104 developmental biology
Microscopy, Fluorescence
Receptors, Androgen
030220 oncology & carcinogenesis
Cancer cell
Cancer research
MCF-7 Cells
Female
RNA Interference
Comet Assay
Tumor Suppressor Protein p53
Developmental Biology
DNA Damage
Subjects
Details
- ISSN :
- 15514005
- Volume :
- 15
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell cycle (Georgetown, Tex.)
- Accession number :
- edsair.doi.dedup.....ef0849d23645e7da4c8a7a9f43f31790