title: Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression.
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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Qiao
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Grabowska
authors.affiliation: Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Forestier-Roman
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Janni
authors.initials: J
authors.lastname: Mirosevich
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Case
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Institute of Imaging Science and Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Renjie
authors.initials: R
authors.lastname: Jin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000726:Androgen Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019886:Gastrin-Releasing Peptide / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000601:surgery; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D018004:Receptors, Bombesin / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide
keywords: GRP/GRP-R; NF-kappa B; androgen receptor variants; progression; prostate cancer