Inhibition of Stearoyl-CoA Desaturase Induces the Unfolded Protein Response in Pancreatic Tumors and Suppresses Their Growth.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Enzyme Inhibitors
/ pharmacology
Gene Expression Regulation, Neoplastic
Humans
Mice, Transgenic
Organoids
Pancreatic Neoplasms
/ drug therapy
Signal Transduction
Stearoyl-CoA Desaturase
/ antagonists & inhibitors
Tumor Burden
/ drug effects
Unfolded Protein Response
/ drug effects
Journal
Pancreas
ISSN: 1536-4828
Titre abrégé: Pancreas
Pays: United States
ID NLM: 8608542
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
entrez:
10
2
2021
pubmed:
11
2
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma is the fourth-leading cause of cancer death in the United States, and there is an urgent need for effective therapies. Stearoyl-CoA desaturase (SCD) is an enzyme localized in the endoplasmic reticulum and generates monounsaturated fatty acid from saturated fatty acid. In this study, we examined the role of SCD in pancreatic cancer. We isolated epithelial cell adhesion molecule-positive pancreatic tumors from the Pdx1Cre;LSL-KrasG12D mouse and formed organoids in Matrigel. Using a SCD inhibitor, A939572, we tested its effects on growth and cell death in tumor organoids, tumors developed in the Pdx1Cre;LSL-KrasG12D mouse, and a human pancreatic ductal adenocarcinoma cell line, PANC-1. A939572 treatment rapidly induced degeneration of mouse tumor organoids and activated the unfolded protein response (UPR). Cotreatment of oleic acid, but not stearic acid, reduced the UPR in the organoids and rescued the inhibitory effect of the SCD inhibitor on their growth. Administration of A939572 to Pdx1Cre;LSL-KrasG12D mice caused cell death in early pancreatic tumors, but not in acini or islets. The SCD inhibitor induced the UPR in PANC-1 and suppressed their growth but did not induce cell death. The inhibition of the SCD enzyme causes an UPR and cell death in early pancreatic tumors.
Identifiants
pubmed: 33565799
doi: 10.1097/MPA.0000000000001737
pii: 00006676-202102000-00015
pmc: PMC7880535
mid: NIHMS1656896
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Stearoyl-CoA Desaturase
EC 1.14.19.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
219-226Subventions
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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