Oncotarget

Research Papers:

Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression

Jingbo Qiao, Magdalena M. Grabowska, Ingrid S. Forestier-Roman, Janni Mirosevich, Thomas C. Case, Dai H. Chung, Justin M.M. Cates, Robert J. Matusik, Charles H. Manning and Renjie Jin _

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Oncotarget. 2016; 7:61955-61969. https://doi.org/10.18632/oncotarget.11326

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Abstract

Jingbo Qiao1,2, Magdalena M. Grabowska1,3, Ingrid S. Forestier-Roman4, Janni Mirosevich1,3, Thomas C. Case1,3, Dai H. Chung1,2, Justin M.M. Cates5, Robert J. Matusik1,3, H. Charles Manning6, Renjie Jin1,3

1Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

2Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

3Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

4Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico

5Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

6Institute of Imaging Science and Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence to:

Renjie Jin, email: [email protected]

Keywords: GRP/GRP-R, NF-kappa B, androgen receptor variants, prostate cancer, progression

Received: April 04, 2016     Accepted: July 27, 2016     Published: August 17, 2016

ABSTRACT

Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone — gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.


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