TY - JOUR
T1 - ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors
AU - Yamashita, Shinichi
AU - Lai, Kuo Pao
AU - Chuang, Kun Lung
AU - Xu, Defeng
AU - Miyamoto, Hiroshi
AU - Tochigi, Tatsuo
AU - Pang, See Tong
AU - Li, Lei
AU - Arai, Yoichi
AU - Kung, Hsing Jien
AU - Yeh, Shuyuan
AU - Chang, Chawnshang
N1 - Funding Information:
Abbreviations: AR, androgen receptor; CRPC, castration-resistant prostate cancer; ADT, androgen deprivation therapy; fAR, full-length AR; shAR3, short-hairpin AR3 Address all correspondence to: Chawnshang Chang, PhD, George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642. E-mail: [email protected] 1ASC-J9 was patented by the University of Rochester, the University of North Carolina, and AndroScience Corp and then licensed to AndroScience Corp. Both the University of Rochester and Chawnshang Chang own royalties and equity in AndroScience Corp. This study was supported by the National Institutes of Health (CA122840 and CA127300), George Whipple Professorship Endowment, and National Science Council, Taiwan Department of Health Clinical Trial, and Research Center of Excellence grant DOH99-TD-B-111-004 (China Medical University, Taichung, Taiwan). 2This article refers to supplementary materials, which are designated by Table W1 and Figures W1 to W6 and are available online at www.neoplasia.com. 3These authors contributed equally. Received 12 October 2011; Revised 20 December 2011; Accepted 22 December 2011 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.111436
PY - 2012/1/1
Y1 - 2012/1/1
N2 - Early studies suggested androgen receptor (AR) splice variants might contribute to the progression of prostate cancer (PCa) into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR) and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown) cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model ofCWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.
AB - Early studies suggested androgen receptor (AR) splice variants might contribute to the progression of prostate cancer (PCa) into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR) and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown) cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model ofCWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.
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U2 - 10.1593/neo.111436
DO - 10.1593/neo.111436
M3 - Article
AN - SCOPUS:84863056052
SN - 1522-8002
VL - 14
SP - 74
EP - 83
JO - Neoplasia
JF - Neoplasia
IS - 1
ER -