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Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration

Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, nove...

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Autores principales: Jeong, Seung Jae, Kim, Jong Hyun, Lim, Beom Jin, Yoon, Ina, Song, Ji-Ae, Moon, Hee-sun, Kim, Doyeun, Lee, Dong Ki, Kim, Sunghoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799795/
https://www.ncbi.nlm.nih.gov/pubmed/29328069
http://dx.doi.org/10.1038/emm.2017.231
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author Jeong, Seung Jae
Kim, Jong Hyun
Lim, Beom Jin
Yoon, Ina
Song, Ji-Ae
Moon, Hee-sun
Kim, Doyeun
Lee, Dong Ki
Kim, Sunghoon
author_facet Jeong, Seung Jae
Kim, Jong Hyun
Lim, Beom Jin
Yoon, Ina
Song, Ji-Ae
Moon, Hee-sun
Kim, Doyeun
Lee, Dong Ki
Kim, Sunghoon
author_sort Jeong, Seung Jae
collection PubMed
description Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, novel therapeutic approaches are highly needed. Intestinal mucin has been known to be affected by dietary threonine supply since de novo synthesis of mucin proteins is sensitive to luminal threonine concentration. However, it is unknown whether biosynthesis of MUC1 is regulated by threonine in human cancers. In this study, data provided suggests that threonine starvation reduces the level of MUC1 and inhibits the migration of MUC1-expressing pancreatic cancer cells. Interestingly, knockdown of threonyl-tRNA synthetase (TRS), an enzyme that catalyzes the ligation of threonine to its cognate tRNA, also suppresses MUC1 levels but not mRNA levels. The inhibitors of TRS decrease the level of MUC1 protein and prohibit the migration of MUC1-expressing pancreatic cancer cells. In addition, a positive correlation between TRS and MUC1 levels is observed in human pancreatic cancer cells. Concurrent with these results, the bioinformatics data indicate that co-expression of both TRS and MUC1 is correlated with the poor survival of pancreatic cancer patients. Taken together, these findings suggest a role for TRS in controlling MUC1-mediated cancer cell migration and provide insight into targeting TRS as a novel therapeutic approach to pancreatic cancer treatment.
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spelling pubmed-57997952018-02-21 Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration Jeong, Seung Jae Kim, Jong Hyun Lim, Beom Jin Yoon, Ina Song, Ji-Ae Moon, Hee-sun Kim, Doyeun Lee, Dong Ki Kim, Sunghoon Exp Mol Med Original Article Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, novel therapeutic approaches are highly needed. Intestinal mucin has been known to be affected by dietary threonine supply since de novo synthesis of mucin proteins is sensitive to luminal threonine concentration. However, it is unknown whether biosynthesis of MUC1 is regulated by threonine in human cancers. In this study, data provided suggests that threonine starvation reduces the level of MUC1 and inhibits the migration of MUC1-expressing pancreatic cancer cells. Interestingly, knockdown of threonyl-tRNA synthetase (TRS), an enzyme that catalyzes the ligation of threonine to its cognate tRNA, also suppresses MUC1 levels but not mRNA levels. The inhibitors of TRS decrease the level of MUC1 protein and prohibit the migration of MUC1-expressing pancreatic cancer cells. In addition, a positive correlation between TRS and MUC1 levels is observed in human pancreatic cancer cells. Concurrent with these results, the bioinformatics data indicate that co-expression of both TRS and MUC1 is correlated with the poor survival of pancreatic cancer patients. Taken together, these findings suggest a role for TRS in controlling MUC1-mediated cancer cell migration and provide insight into targeting TRS as a novel therapeutic approach to pancreatic cancer treatment. Nature Publishing Group 2018-01 2018-01-12 /pmc/articles/PMC5799795/ /pubmed/29328069 http://dx.doi.org/10.1038/emm.2017.231 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Jeong, Seung Jae
Kim, Jong Hyun
Lim, Beom Jin
Yoon, Ina
Song, Ji-Ae
Moon, Hee-sun
Kim, Doyeun
Lee, Dong Ki
Kim, Sunghoon
Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title_full Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title_fullStr Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title_full_unstemmed Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title_short Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration
title_sort inhibition of muc1 biosynthesis via threonyl-trna synthetase suppresses pancreatic cancer cell migration
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799795/
https://www.ncbi.nlm.nih.gov/pubmed/29328069
http://dx.doi.org/10.1038/emm.2017.231
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