Oncotarget

Research Papers:

Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice

Min Wu, Sahn-Ho Kim, Indrani Datta, Albert Levin, Gregory Dyson, Jing Li, Stephanie Kaypee, M. Mahadeva Swamy, Nilesh Gupta, Ho Jeong Kwon, Mani Menon, Tapas K. Kundu and G. Prem-Veer Reddy _

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Oncotarget. 2015; 6:6136-6150. https://doi.org/10.18632/oncotarget.3346

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Abstract

Min Wu1, Sahn-Ho Kim1, Indrani Datta2, Albert Levin2, Gregory Dyson3, Jing Li4, Stephanie Kaypee5, M. Mahadeva Swamy5, Nilesh Gupta6, Ho Jeong Kwon7, Mani Menon1, Tapas K. Kundu5 and G. Prem-Veer Reddy1

1 Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA

2 Bioinformatics Core, Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA

3 Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

4 Pharmacology Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

5 Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Bangalore, Karnataka, India

6 Department of Pathology, Henry Ford Hospital, Detroit, MI, USA

7 Department of Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea

Correspondence:

G. Prem Veer Reddy, email:

Keywords: Androgen receptor, calmodulin, Hydrazinobenzoylcurcumin, CTK7A, castration-resistant prostate cancer

Received: November 24, 2014 Accepted: January 20, 2015 Published: January 31, 2015

Abstract

There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC.


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