Back to Search
Start Over
Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling
- Source :
- Cell Reports, Vol 18, Iss 8, Pp 1970-1981 (2017)
- Publication Year :
- 2017
- Publisher :
- Elsevier, 2017.
-
Abstract
- Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.
- Subjects :
- 0301 basic medicine
Cell cycle checkpoint
DNA damage
Chk1
Biology
CDC6
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
chemistry.chemical_compound
Prostate cancer
androgen receptor
medicine
Enzalutamide
CHEK1
Androgen Receptor Antagonists
lcsh:QH301-705.5
enzalutamide
medicine.disease
prostate cancer
AZD7762
3. Good health
Androgen receptor
030104 developmental biology
ATR
chemistry
lcsh:Biology (General)
Cancer research
Signal transduction
biological phenomena, cell phenomena, and immunity
TOPBP1
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 18
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....ccf66825fcda31b68eade1ff4b07e5d1