Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer

Autor: Laine Heidman, Fiorella Magani, Kerry L. Burnstein, Chen Hao Lo, Meghan A. Rice, Yushan Zhang, Maria J. Martinez, Stephanie Peacock, Yehia Daaka, Conor C. Lynch, Cale D. Fahrenholtz, Valeria A. Copello, Ann M. Greene, Ning Zhao
Rok vydání: 2018
Předmět:
MAPK/ERK pathway
Male
Receptors
Vasopressin
desmopressin
Indoles
Pyrrolidines
medicine.drug_class
MAP Kinase Signaling System
vasopressin
Mice
Nude
urologic and male genital diseases
relcovaptan
Article
Androgen deprivation therapy
Prostate cancer
Castration Resistance
Osteogenesis
Cell Line
Tumor
Medicine
Animals
Humans
Molecular Targeted Therapy
RNA
Messenger
Receptor
Cyclic AMP Response Element-Binding Protein
Proto-Oncogene Proteins c-vav
Cell Proliferation
Arginine vasopressin receptor 1A
drug repurposing
business.industry
General Commentary
General Medicine
Androgen
medicine.disease
hormone-resistant cancer
Androgen receptor
Gene Expression Regulation
Neoplastic
Prostatic Neoplasms
Castration-Resistant
Oncology
Drug Resistance
Neoplasm
Receptors
Androgen
Cancer research
Calcium
business
Zdroj: Frontiers in Oncology
Sci Transl Med
ISSN: 1946-6242
Popis: Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein–coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.
Databáze: OpenAIRE
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