TY - JOUR
T1 - Anticancer imidazoacridinone C-1311 is effective in androgen-dependent and androgen-independent prostate cancer cells
AU - Niemira, Magdalena
AU - Borowa-Mazgaj, Barbara
AU - Bader, Samuel B.
AU - Moszyńska, Adrianna
AU - Ratajewski, Marcin
AU - Karaś, Kaja
AU - Kwaśniewski, Miroslaw
AU - Kretowski, Adam
AU - Mazerska, Zofia
AU - Hammond, Ester M.
AU - Skwarska, Anna
N1 - Publisher Copyright:
© 2020 by the authors.
PY - 2020/9
Y1 - 2020/9
N2 - The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.
AB - The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.
KW - Androgen receptor
KW - C-1311/Symadex™
KW - Next-generation sequencing
KW - Prostate cancer
KW - Transcriptomic profiling
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U2 - 10.3390/BIOMEDICINES8090292
DO - 10.3390/BIOMEDICINES8090292
M3 - Article
AN - SCOPUS:85090201476
SN - 2227-9059
VL - 8
JO - Biomedicines
JF - Biomedicines
IS - 9
M1 - 292
ER -