Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
Metrics: PDF 1212 views | HTML 1496 views | ?
Shao Jian Lin1,*, Zhi Gen Leng2,*, Yu Hang Guo2,*, Lin Cai2, Yu Cai1, Ning Li1, Han Bing Shang1, Wei-Dong Le3, Wei Guo Zhao1, Zhe Bao Wu1
1Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
3Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
*These authors have contributed equally to this work
Zhe Bao Wu, e-mail: email@example.com
Wei Guo Zhao, e-mail: firstname.lastname@example.org
Keywords: autophagy, cabergoline, prolactinoma, autophagic cell death, autophagic flux
Received: July 07, 2015 Accepted: September 17, 2015 Published: October 16, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.