Cargando…

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

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 C...

Descripción completa

Detalles Bibliográficos
Autores principales: Lin, Shao Jian, Leng, Zhi Gen, Guo, Yu Hang, Cai, Lin, Cai, Yu, Li, Ning, Shang, Han Bing, Le, Wei-Dong, Zhao, Wei Guo, Wu, Zhe Bao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770775/
https://www.ncbi.nlm.nih.gov/pubmed/26513171
_version_ 1782418332878635008
author Lin, Shao Jian
Leng, Zhi Gen
Guo, Yu Hang
Cai, Lin
Cai, Yu
Li, Ning
Shang, Han Bing
Le, Wei-Dong
Zhao, Wei Guo
Wu, Zhe Bao
author_facet Lin, Shao Jian
Leng, Zhi Gen
Guo, Yu Hang
Cai, Lin
Cai, Yu
Li, Ning
Shang, Han Bing
Le, Wei-Dong
Zhao, Wei Guo
Wu, Zhe Bao
author_sort Lin, Shao Jian
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4770775
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-47707752016-03-21 Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline Lin, Shao Jian Leng, Zhi Gen Guo, Yu Hang Cai, Lin Cai, Yu Li, Ning Shang, Han Bing Le, Wei-Dong Zhao, Wei Guo Wu, Zhe Bao Oncotarget Research Paper 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. Impact Journals LLC 2015-10-14 /pmc/articles/PMC4770775/ /pubmed/26513171 Text en Copyright: © 2015 Lin et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lin, Shao Jian
Leng, Zhi Gen
Guo, Yu Hang
Cai, Lin
Cai, Yu
Li, Ning
Shang, Han Bing
Le, Wei-Dong
Zhao, Wei Guo
Wu, Zhe Bao
Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title_full Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title_fullStr Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title_full_unstemmed Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title_short Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline
title_sort suppression of mtor pathway and induction of autophagy-dependent cell death by cabergoline
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770775/
https://www.ncbi.nlm.nih.gov/pubmed/26513171
work_keys_str_mv AT linshaojian suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT lengzhigen suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT guoyuhang suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT cailin suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT caiyu suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT lining suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT shanghanbing suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT leweidong suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT zhaoweiguo suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline
AT wuzhebao suppressionofmtorpathwayandinductionofautophagydependentcelldeathbycabergoline