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

// Jingbo Qiao 1, 2 , Magdalena M. Grabowska 1, 3 , Ingrid S. Forestier-Roman 4 , Janni Mirosevich 1, 3 , Thomas C. Case 1, 3 , Dai H. Chung 1, 2 , Justin M.M. Cates 5 , Robert J. Matusik 1, 3 , H. Charles Manning 6 , Renjie Jin 1, 3 1 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA 2 Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA 3 Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA 4 Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 5 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA 6 Institute of Imaging Science and Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, USA Correspondence to: Renjie Jin, email: renjie.jin@vanderbilt.edu 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.