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Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline

Shao Jian Lin1, Zhi Gen Leng2, Yu Hang Guo2

  • 1Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Oncotarget
|October 30, 2015
PubMed

Insights

Cabergoline (CAB) induces autophagy and blocks its flux, leading to cell death in prolactinomas. This novel mechanism explains CAB

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Endocrinology

Background:

  • Cabergoline (CAB) is a first-line treatment for prolactinomas, effectively reducing prolactin levels and tumor size.
  • The precise mechanisms underlying CAB's tumor-shrinking effects remain largely unelucidated.

Purpose of the Study:

  • To investigate the novel cytotoxic mechanisms of Cabergoline (CAB) in prolactinoma cells.
  • To explore the role of autophagy and autophagic flux in CAB-mediated anti-tumor activity.

Main Methods:

  • Induction of autophagy by CAB in rat pituitary tumor cell lines (MMQ and GH3) via mTOR pathway inhibition.
  • Assessment of autophagosome formation, LC3 conversion, and p62 aggregation.
  • Evaluation of CAB's effect on lysosomal acidification and proteolytic degradation.
  • Analysis of CAB-induced cell death following knockdown of autophagy-related genes (ATG7, ATG5, Becn1).
  • In vivo studies to confirm the role of autophagy and autophagic flux blockade in anti-tumoral action.

Main Results:

  • CAB treatment initiated autophagosome formation by inhibiting the mTOR pathway, evidenced by increased LC3-II conversion and GFP-LC3 puncta.
  • CAB augmented lysosome acidification, impairing proteolytic degradation and blocking autophagic flux, leading to p62 accumulation.
  • Genetic inhibition of key autophagy genes (ATG7, ATG5, Becn1) significantly rescued CAB-induced cell death.
  • CAB-induced autophagy and autophagic flux blockade were confirmed to contribute to anti-tumoral effects in vivo.

Conclusions:

  • Cabergoline (CAB) exerts its anti-proliferative effects by simultaneously inducing autophagy and inhibiting autophagic flux.
  • This dual action leads to autophagy-dependent cell death in prolactinoma cells.
  • The findings reveal a novel cytotoxic mechanism for CAB, offering potential therapeutic insights.
Keywords:
autophagic cell deathautophagic fluxautophagycabergolineprolactinoma

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