TY - JOUR
T1 - Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7
AU - Chandrasekaran, Balaji
AU - Tyagi, Ashish
AU - Saran, Uttara
AU - Kolluru, Venkatesh
AU - Baby, Becca V.
AU - Chirasani, Venkat R.
AU - Dokholyan, Nikolay V.
AU - Lin, Jyh M.
AU - Singh, Amandeep
AU - Sharma, Arun K.
AU - Ankem, Murali K.
AU - Damodaran, Chendil
N1 - Publisher Copyright:
Copyright © 2023 Chandrasekaran, Tyagi, Saran, Kolluru, Baby, Chirasani, Dokholyan, Lin, Singh, Sharma, Ankem and Damodaran.
PY - 2023
Y1 - 2023
N2 - We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.
AB - We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR− CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.
UR - http://www.scopus.com/inward/record.url?scp=85150428593&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150428593&partnerID=8YFLogxK
U2 - 10.3389/fphar.2023.1137783
DO - 10.3389/fphar.2023.1137783
M3 - Article
C2 - 36937838
AN - SCOPUS:85150428593
SN - 1663-9812
VL - 14
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1137783
ER -