ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin

Daria Fleyshman, Peter Cheney, Anda Ströse, Shaila Mudambi, Alfiya Safina, Mairead Commane, Andrei Purmal, Kelsey Morgan, Nicholas J. Wang, Joe Gray, Paul Spellman, Natalia Issaeva, Katerina Gurova

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)455-470
Number of pages16
JournalCell Cycle
Volume15
Issue number3
DOIs
StatePublished - Feb 1 2016

Fingerprint

Androgen Receptors
DNA Damage
Prostatic Neoplasms
Breast Neoplasms
Androgens
Death Domain Receptors
Double-Stranded DNA Breaks
Poisons
Neoplasms
Epithelial Cells

Keywords

  • androgen receptor
  • ARTIK-52
  • breast cancer
  • DNA damage
  • p53
  • prostate cancer

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Fleyshman, D., Cheney, P., Ströse, A., Mudambi, S., Safina, A., Commane, M., ... Gurova, K. (2016). ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin. Cell Cycle, 15(3), 455-470. https://doi.org/10.1080/15384101.2015.1127478

ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin. / Fleyshman, Daria; Cheney, Peter; Ströse, Anda; Mudambi, Shaila; Safina, Alfiya; Commane, Mairead; Purmal, Andrei; Morgan, Kelsey; Wang, Nicholas J.; Gray, Joe; Spellman, Paul; Issaeva, Natalia; Gurova, Katerina.

In: Cell Cycle, Vol. 15, No. 3, 01.02.2016, p. 455-470.

Research output: Contribution to journalArticle

Fleyshman, D, Cheney, P, Ströse, A, Mudambi, S, Safina, A, Commane, M, Purmal, A, Morgan, K, Wang, NJ, Gray, J, Spellman, P, Issaeva, N & Gurova, K 2016, 'ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin', Cell Cycle, vol. 15, no. 3, pp. 455-470. https://doi.org/10.1080/15384101.2015.1127478
Fleyshman, Daria ; Cheney, Peter ; Ströse, Anda ; Mudambi, Shaila ; Safina, Alfiya ; Commane, Mairead ; Purmal, Andrei ; Morgan, Kelsey ; Wang, Nicholas J. ; Gray, Joe ; Spellman, Paul ; Issaeva, Natalia ; Gurova, Katerina. / ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin. In: Cell Cycle. 2016 ; Vol. 15, No. 3. pp. 455-470.
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