title: Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline.
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.
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shao Jian
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Zhi Gen
authors.initials: ZG
authors.lastname: Leng
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Yu Hang
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Han Bing
authors.initials: HB
authors.lastname: Shang
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Le
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei Guo
authors.initials: WG
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhe Bao
authors.initials: ZB
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000077465:Cabergoline; D016923:Cell Death / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D051379:Mice; D008819:Mice, Nude; D015175:Prolactinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D004873:Ergolines; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000077465:Cabergoline
keywords: autophagic cell death; autophagic flux; autophagy; cabergoline; prolactinoma