Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer

Abstract Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the rece...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ru Chen, Lisa A Lai, Yumi Sullivan, Melissa Wong, Lei Wang, Jonah Riddell, Linda Jung, Venu G. Pillarisetty, Teresa A. Brentnall, Sheng Pan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4330feb75977443b89a09ae113dbd509
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4330feb75977443b89a09ae113dbd509
record_format	dspace
spelling	oai:doaj.org-article:4330feb75977443b89a09ae113dbd5092021-12-02T11:52:22ZDisrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer10.1038/s41598-017-08436-62045-2322https://doaj.org/article/4330feb75977443b89a09ae113dbd5092017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08436-6https://doaj.org/toc/2045-2322Abstract Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.Ru ChenLisa A LaiYumi SullivanMelissa WongLei WangJonah RiddellLinda JungVenu G. PillarisettyTeresa A. BrentnallSheng PanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ru Chen Lisa A Lai Yumi Sullivan Melissa Wong Lei Wang Jonah Riddell Linda Jung Venu G. Pillarisetty Teresa A. Brentnall Sheng Pan Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
description	Abstract Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.
format	article
author	Ru Chen Lisa A Lai Yumi Sullivan Melissa Wong Lei Wang Jonah Riddell Linda Jung Venu G. Pillarisetty Teresa A. Brentnall Sheng Pan
author_facet	Ru Chen Lisa A Lai Yumi Sullivan Melissa Wong Lei Wang Jonah Riddell Linda Jung Venu G. Pillarisetty Teresa A. Brentnall Sheng Pan
author_sort	Ru Chen
title	Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
title_short	Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
title_full	Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
title_fullStr	Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
title_full_unstemmed	Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
title_sort	disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4330feb75977443b89a09ae113dbd509
work_keys_str_mv	AT ruchen disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT lisaalai disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT yumisullivan disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT melissawong disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT leiwang disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT jonahriddell disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT lindajung disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT venugpillarisetty disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT teresaabrentnall disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer AT shengpan disruptingglutaminemetabolicpathwaystosensitizegemcitabineresistantpancreaticcancer
_version_	1718395043295789056

Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer

Ejemplares similares