Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
Shao Jian Lin, Zhi Gen Leng, Yu Hang Guo, Lin Cai, Yu Cai, Ning Li, Han Bing Shang, Wei-Dong Le, Wei Guo Zhao, Zhe Bao Wu, Shao Jian Lin, Zhi Gen Leng, Yu Hang Guo, Lin Cai, Yu Cai, Ning Li, Han Bing Shang, Wei-Dong Le, Wei Guo Zhao, Zhe Bao Wu
Abstract
Cabergoline (CAB), the first-line drug for treatment of prolactinomas, is effective in suppressing prolactin hypersecretion, reducing tumor size, and restoring gonadal function. However, mechanisms for CAB-mediated tumor shrinkage are largely unknown. Here we report a novel cytotoxic mechanism for CAB. CAB induced formation of autophagosome in rat pituitary tumor MMQ and GH3 cells at the early stage through inhibiting mTOR pathway, resulting in higher conversion rates of LC3-I to LC3-II, GFP-LC3 aggregation, and increased autophagosome formation. Interestingly, CAB treatment augmented lysosome acidification and resulted in impaired proteolytic degradation within autolysosomes. This blocked the autophagic flux, leading to the accumulation of p62 aggregation and undigested autolysosomes. Knockdown of ATG7, ATG5, or Becn1, could significantly rescue the CAB-mediated cell death of MMQ cells (p < 0.05). CAB-induced autophagy and blockade of autophagy flux participated in antitumoral action in vivo. In conclusion, our study provides evidence that CAB concomitantly induces autophagy and inhibits the autophagic flux, leading to autophagy-dependent cell death. These findings elucidate novel mechanisms for CAB action.
Keywords: autophagic cell death; autophagic flux; autophagy; cabergoline; prolactinoma.
Conflict of interest statement
CONFLICTS OF INTEREST
No potential conflicts of interest were disclosed.
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References
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