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.

Details

Title
Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
Author
Chen, Ru 1 ; Lai, Lisa A 1 ; Sullivan, Yumi 1 ; Wong, Melissa 1 ; Wang, Lei 1 ; Riddell, Jonah 2 ; Jung, Linda 2 ; Pillarisetty, Venu G 3   VIAFID ORCID Logo  ; Brentnall, Teresa A 1 ; Pan, Sheng 1 

 Department of Medicine, University of Washington, Seattle, WA, USA 
 Cell Signaling Technology, Inc, Danvers, MA, USA 
 Department of Surgery, University of Washington, Seattle, WA, USA 
Pages
1-14
Publication year
2017
Publication date
Aug 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1957201682
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.