Abstract

Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Results of the present work clearly show that androgens can specifically act at the membrane level via the GPCR oxoeicosanoid receptor 1 (OXER1) in prostate cancer cells. In fact, OXER1 expression parallels that of membrane androgen binding in prostate cancer cell lines and tumor specimens, while in silico docking simulation of OXER1 showed that testosterone could bind to OXER1 within the same grove as 5-OxoETE, the natural ligand of OXER1. Interestingly, testosterone antagonizes the effects of 5-oxoETE on specific signaling pathways and rapid effects such as actin cytoskeleton reorganization that ultimately can modulate cell migration and metastasis. These findings verify that membrane-acting androgens exert specific effects through an antagonistic interaction with OXER1. Additionally, this interaction between androgen and OXER1, which is an arachidonic acid metabolite receptor expressed in prostate cancer, provides a novel link between steroid and lipid actions and renders OXER1 as new player in the disease. These findings should be taken into account in the design of novel therapeutic approaches in prostate cancer.

Highlights

  • Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis

  • This protein corresponds to the oxoeicosanoid receptor 1 (OXER1 or GPR170) with a molecular weight of 46 KD

  • A search in the evolutionary conserved regions database revealed that OXER1 is conserved in primates (100%), with a partial conservation (48%) in opossum, but it is absent in canines, rodents, birds and lower vertebrates, suggesting that this testosterone-OXER1 interaction is specific to primates (Supplementary Figure S1)

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Summary

Introduction

Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Testosterone antagonizes the effects of 5-oxoETE on specific signaling pathways and rapid effects such as actin cytoskeleton reorganization that can modulate cell migration and metastasis These findings verify that membrane-acting androgens exert specific effects through an antagonistic interaction with OXER1. This interaction between androgen and OXER1, which is an arachidonic acid metabolite receptor expressed in prostate cancer, provides a novel link between steroid and lipid actions and renders OXER1 as new player in the disease. Recent publications have identified two different GPCR proteins with characteristics of membrane androgen receptors: the G Protein-Coupled Receptor Family C Group 6 Member A19–21 and the zinc transporter protein, ZIP922

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