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Title:
Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer | Scientific Reports
Description:
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.
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nature portfolio scientific instrument services activating hab18g/cd147-egfr-pstat3 signaling privacy policy phospho-stat3 kits advertising nature 496 nature 316 nature chemical tools software solutions reprints author information authors ubiquitin-mediated proteasomal degradation drug-resistant human adenocarcinoma pancreatic ductal adenocarcinoma sensitize chemo-resistant pdac 6-diazo-5-oxo-l-norleucine alexa568 goat anti-rabbit stable-isotope dimethyl labeling disrupting n-linked glycosylation original author serum-free media atop gemcitabine-metal–organic frameworks n-linked glycosylation sites serine/threonine-protein kinases provide udp-n-acetylglucosamine receptor tyrosine kinases phospho-p44/p42 mapk vivo drug-induced apoptosis 100 mg/ml fibronectin overnight tandem mass spectrometry thermo fisher scientific mass spectrometry analysis permissions smad3/cmyc axis key gemcitabine-metabolising enzyme potential anti-cancer activity kras-regulated metabolic pathway hexosamine biosynthetic pathway chemoresistant pancreatic cancer full size image trans-proteomic pipeline egfr-related signaling pathways suppress udp-glcnac generation phospho-s6 ribosomal protein site-specific glycosylation occupancy mass spectrometric data proteomics data analysis pancreatic cancer survival
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headline:Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
description: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.
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Cancer therapeutic resistance
Mass spectrometry
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headline:Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
description: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.
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