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Cholesterol-activated stress granules reduce the membrane localization of DRD2 and promote prolactinoma dopamine agonists resistance

  • 0Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 183 Xinqiao Main Street, Shapingba District, Chongqing, China.
Acta Neuropathologica Communications +

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April 25, 2025

|

April 25, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Cholesterol metabolism abnormalities contribute to dopamine agonist resistance in prolactinoma by affecting dopamine D2 receptor localization. Targeting stress granule formation may overcome this resistance.

Area Of Science

  • Endocrinology
  • Oncology
  • Molecular Biology

Background

  • Prolactinoma, the most common pituitary neuroendocrine tumor, is typically treated with dopamine agonists (DAs).
  • Dopamine agonist resistance is a significant clinical challenge, limiting treatment efficacy for some patients.

Purpose Of The Study

  • To investigate the role of cholesterol metabolism in dopamine agonist resistance in prolactinoma.
  • To elucidate the molecular mechanisms underlying cholesterol-induced resistance.

Main Methods

  • Transcriptome sequencing of surgical prolactinoma samples.
  • In vitro and in vivo experiments using prolactinoma cell lines and xenografts.
  • Immunoprecipitation combined with mass spectrometry, Western blot, and fluorescent probe assays.
  • Interference with stress granule formation using genetic and small molecule approaches.
  • Drug repositioning analysis to identify potential therapeutic agents.

Main Results

  • Abnormal cholesterol metabolism was identified in prolactinoma, particularly in DA-resistant tumors.
  • Cholesterol exposure enhanced resistance to cabergoline in prolactinoma cells and xenografts.
  • Cholesterol altered dopamine D2 receptor distribution, decreasing membrane abundance and increasing cytoplasmic localization.
  • Cholesterol promoted the formation of stress granules by increasing the binding affinity between DRD2 and G3BP1.
  • Interfering with stress granule formation reversed cholesterol-induced DA resistance.
  • Anisomycin, a stress granule inhibitor, attenuated cholesterol-induced cabergoline resistance.

Conclusions

  • Abnormal cholesterol metabolism contributes to dopamine agonist resistance in prolactinoma.
  • This resistance is mediated by cholesterol-induced stress granule formation, which disrupts dopamine D2 receptor membrane localization.
  • Targeting stress granule pathways presents a potential therapeutic strategy to overcome dopamine agonist resistance in prolactinoma.

Keywords:

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