Oncotarget

Research Papers:

Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening

Cheng-Lung Hsu _, Jai-Shin Liu, Ting-Wei Lin, Ying-Hsu Chang, Yung-Chia Kuo, An-Chi Lin, Huei-Ju Ting, See-Tong Pang, Li-Yu Lee, Wen-Lung Ma, Chun-Cheng Lin and Wen-Guey Wu

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Oncotarget. 2017; 8:69508-69519. https://doi.org/10.18632/oncotarget.17843

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Abstract

Cheng-Lung Hsu1, Jai-Shin Liu2, Ting-Wei Lin3, Ying-Hsu Chang4, Yung-Chia Kuo1, An-Chi Lin1, Huei-Ju Ting5, See-Tong Pang4, Li-Yu Lee6, Wen-Lung Ma7, Chun-Cheng Lin3 and Wen-Guey Wu2

1Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

2Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan

3Department of Chemistry, National Tsing-Hua University, Hsinchu 300, Taiwan

4Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

5Department of Biological Science and Technology, National University of Tainan, Tainan 700, Taiwan

6Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

7Sex Hormone Research Center, China Medical University Hospital, Taichung 104, Taiwan

Correspondence to:

Cheng-Lung Hsu, email: [email protected]

Wen-Guey Wu, email: [email protected]

Chun-Cheng Lin, email: [email protected]

Keywords: FxxLF, RIPK1, androgen receptor, prostate cancer, oxadiazole

Received: November 04, 2016     Accepted: April 27, 2017     Published: May 13, 2017

ABSTRACT

Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.


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