The following is a summary of “Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: possible mechanisms involved,” published in the September 2024 issue of Endocrinology by Malamos et al.

OXER1, the receptor for the arachidonic acid metabolite 5-oxo-eicosatetraenoic acid (5-oxo-ETE), has traditionally been understood to function as a G protein-coupled receptor (GPCR) localized on the plasma membrane. It is well-documented that OXER1 mediates a variety of cellular signaling pathways, including those that influence cancer cell proliferation and migration. Interestingly, recent evidence suggests that OXER1 can also bind and mediate the membrane-initiated actions of androgens, which antagonize the effects of 5-oxo-ETE through this receptor. The objective of the study was to explore the potential localization of OXER1 within the nucleus and to elucidate the mechanisms that facilitate this nuclear translocation.

Using immunofluorescence and western blot analyses, researchers confirmed the presence of OXER1 in the nuclei of two prostate cancer cell lines (DU-145 and LNCaP) as well as in Chinese hamster ovary (CHO) cells transfected with a GFP-labeled OXER1 construct. These experiments were conducted under both untreated conditions and in the presence of OXER1 ligands. To establish the necessity of ligand binding for nuclear translocation, the study group utilized CHO cells expressing a mutated OXER1-GFP that was incapable of binding 5-oxo-ETE. Furthermore, in silico analysis identified nuclear localization signal (NLS) sequences within OXER1, and the role of these sequences was investigated using specific inhibitors and siRNAs targeting importins, which are known to mediate cytoplasmic-nuclear transport.

Additionally, investigators examined the role of receptor palmitoylation in OXER1 nuclear translocation. Potential palmitoylation sites were identified in silico, and the involvement of palmitoylation was tested using a specific palmitoylation inhibitor. The findings demonstrate that OXER1 is indeed capable of nuclear localization in an agonist-dependent manner, a process that is inhibited by androgens. The study group identified two potential mechanisms for OXER1 nuclear trafficking: one involving receptor palmitoylation and the other mediated by importin-dependent cytoplasmic-nuclear transport.

To their knowledge, this study is the first to report the nuclear localization of a membrane androgen receptor, highlighting an alternative and more direct mode of androgen action that involves nuclear mechanisms. These novel insights into androgen-mediated actions and androgen-lipid interactions not only expand the understanding of OXER1’s role in cellular signaling but also reveal new potential therapeutic targets for treating cancer and other pathological conditions in which OXER1 plays a significant role.

Source: sciencedirect.com/science/article/abs/pii/S0303720724002132