Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells

Dysregulation of Hedgehog (Hh) signaling pathway is one of the hallmarks of pancreatic ductal adenocarcinoma (PDA). Lithium, a clinical mood stabilizer for the treatment of mental disorders, is known to suppress tumorigenic potential of PDA cells by targeting the Hh/Gli signaling pathway. In this st...

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Autores principales: Wang, Xinshuo, Fang, Zijian, Wang, Anlin, Luo, Cheng, Cheng, Xiaodong, Lu, Meiling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Pharmacology
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715333/
https://www.ncbi.nlm.nih.gov/pubmed/29249966
http://dx.doi.org/10.3389/fphar.2017.00820
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author Wang, Xinshuo
Fang, Zijian
Wang, Anlin
Luo, Cheng
Cheng, Xiaodong
Lu, Meiling
author_facet Wang, Xinshuo
Fang, Zijian
Wang, Anlin
Luo, Cheng
Cheng, Xiaodong
Lu, Meiling
author_sort Wang, Xinshuo
collection PubMed
description Dysregulation of Hedgehog (Hh) signaling pathway is one of the hallmarks of pancreatic ductal adenocarcinoma (PDA). Lithium, a clinical mood stabilizer for the treatment of mental disorders, is known to suppress tumorigenic potential of PDA cells by targeting the Hh/Gli signaling pathway. In this study, we investigated the molecular mechanism of lithium induced down-regulation of Hh/Gli1. Our data show that lithium promotes the poly-ubiquitination and proteasome-mediated degradation of Gli1 through activating E3 ligase ITCH. Additionally, lithium enhances interaction between Gli1 and SUFU via suppressing GSK3β, which phosphorylates SUFU and destabilizes the SUFU-Gli1 inhibitory complex. Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH-dependent Gli1 ubiquitination/degradation and SUFU-mediated Gli1 inhibition.
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spelling pubmed-57153332017-12-15 Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells Wang, Xinshuo Fang, Zijian Wang, Anlin Luo, Cheng Cheng, Xiaodong Lu, Meiling Front Pharmacol Pharmacology Dysregulation of Hedgehog (Hh) signaling pathway is one of the hallmarks of pancreatic ductal adenocarcinoma (PDA). Lithium, a clinical mood stabilizer for the treatment of mental disorders, is known to suppress tumorigenic potential of PDA cells by targeting the Hh/Gli signaling pathway. In this study, we investigated the molecular mechanism of lithium induced down-regulation of Hh/Gli1. Our data show that lithium promotes the poly-ubiquitination and proteasome-mediated degradation of Gli1 through activating E3 ligase ITCH. Additionally, lithium enhances interaction between Gli1 and SUFU via suppressing GSK3β, which phosphorylates SUFU and destabilizes the SUFU-Gli1 inhibitory complex. Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH-dependent Gli1 ubiquitination/degradation and SUFU-mediated Gli1 inhibition. Frontiers Media S.A. 2017-11-16 /pmc/articles/PMC5715333/ /pubmed/29249966 http://dx.doi.org/10.3389/fphar.2017.00820 Text en Copyright © 2017 Wang, Fang, Wang, Luo, Cheng and Lu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Xinshuo
Fang, Zijian
Wang, Anlin
Luo, Cheng
Cheng, Xiaodong
Lu, Meiling
Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title_full Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title_fullStr Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title_full_unstemmed Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title_short Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells
title_sort lithium suppresses hedgehog signaling via promoting itch e3 ligase activity and gli1–sufu interaction in pda cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715333/
https://www.ncbi.nlm.nih.gov/pubmed/29249966
http://dx.doi.org/10.3389/fphar.2017.00820
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