NDLI: Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Palam, L. R. Gore, J. Craven, K. E. Wilson, J. L. Korc, M.
Description	Country affiliation: United States Author Affiliation: Palam LR ( Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and The Center for Pancreatic Cancer Research, Indianapolis, IN, USA.); Gore J ( Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and The Center for Pancreatic Cancer Research, Indianapolis, IN, USA.); Craven KE ( Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and The Center for Pancreatic Cancer Research, Indianapolis, IN, USA.); Wilson JL ( Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and The Center for Pancreatic Cancer Research, Indianapolis, IN, USA.); Korc M ( Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and The Center for Pancreatic Cancer Research, Indianapolis, IN, USA.)
Abstract	Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with marked chemoresistance and a 5-year survival rate of 7%. The integrated stress response (ISR) is a cytoprotective pathway initiated in response to exposure to various environmental stimuli. We used pancreatic cancer cells (PCCs) that are highly resistant to gemcitabine (Gem) and an orthotopic mouse model to investigate the role of the ISR in Gem chemoresistance. Gem induced eIF2 phosphorylation and downstream transcription factors ATF4 and CHOP in PCCs, and these effects occurred in an eIF2 -S51 phosphorylation-dependent manner as determined using PANC-1 cells, and wild type and S51 mutant mouse embryo fibroblasts. Blocking the ISR pathway in PCCs with the ISR inhibitor ISRIB or siRNA-mediated depletion of ATF4 resulted in enhanced Gem-mediated apoptosis. Polyribosomal profiling revealed that Gem caused repression of global translation and this effect was reversed by ISRIB or by expressing GADD34 to facilitate eIF2 dephosphorylation. Moreover, Gem promoted preferential mRNA translation as determined in a TK-ATF4 5'UTR-Luciferase reporter assay, and this effect was also reversed by ISRIB. RNA-seq analysis revealed that Gem upregulated eIF2 and Nrf2 pathways, and that ISRIB significantly inhibited these pathways. Gem also induced the expression of the antiapoptotic factors Nupr1, BEX2, and Bcl2a1, whereas ISRIB reduced their expression. In an orthotopic tumor model using PANC-1 cells, ISRIB facilitated Gem-mediated increases in PARP cleavage, which occurred in conjunction with decreased tumor size. These findings indicate that Gem chemoresistance is enhanced by activating multiple ISR-dependent pathways, including eIF2, Nrf2, Nupr1, BEX2, and Bcl2A1. It is suggested that targeting the ISR pathway may be an efficient mechanism for enhancing therapeutic responsiveness to Gem in PDAC.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2015.264
Journal	Cell Death and Disease
Volume Number	6
Language	English
Publisher	Nature Publishing Group
Publisher Date	2015-10-15
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Protein Biosynthesis Oxidative Stress Carcinoma, Pancreatic Ductal Transcriptome Activating Transcription Factor 4 Drug Resistance, Neoplasm Neoplasm Proteins Genetics Acetamides Pancreatic Neoplasms Protein Phosphatase 1 Gene Expression Signal Transduction Drug Therapy Pharmacology Metabolism Cyclohexylamines Xenograft Model Antitumor Assays Discipline Cell Biology Basic Helix-loop-helix Transcription Factors Animals Deoxycytidine Mice, Nude Cell Line, Tumor Antimetabolites, Antineoplastic Analogs & Derivatives
Content Type	Text
Resource Type	Article

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in