دورية أكاديمية
أعرض في EDS

Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.

التفاصيل البيبلوغرافية
العنوان: Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.
المؤلفون: Kim JH; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Lee J; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Im SS; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Kim B; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Kim EY; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Min HJ; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Heo J; Department of Cell and Genetic Engineering, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Chang EJ; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Choi KC; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Shin DM; Department of Cell and Genetic Engineering, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea., Son J; Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea. jaekson@amc.seoul.kr.
المصدر: Experimental & molecular medicine [Exp Mol Med] 2024 Apr; Vol. 56 (4), pp. 1013-1026. Date of Electronic Publication: 2024 Apr 30.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9607880 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2092-6413 (Electronic) Linking ISSN: 12263613 NLM ISO Abbreviation: Exp Mol Med Subsets: MEDLINE
أسماء مطبوعة: Publication: Jan. 2013- : New York : Nature Publishing Group
Original Publication: Seoul : Korean Society of Medical Biochemistry and Molecular Biology, 1996-
مواضيع طبية MeSH: CASP8 and FADD-Like Apoptosis Regulating Protein*/metabolism , CASP8 and FADD-Like Apoptosis Regulating Protein*/genetics , TNF-Related Apoptosis-Inducing Ligand*/metabolism , Epigenesis, Genetic* , Glutamine*/metabolism , Jumonji Domain-Containing Histone Demethylases*/metabolism , Jumonji Domain-Containing Histone Demethylases*/genetics , Drug Resistance, Neoplasm*/genetics , Pancreatic Neoplasms*/metabolism , Pancreatic Neoplasms*/genetics , Pancreatic Neoplasms*/pathology , Gene Expression Regulation, Neoplastic*/drug effects , Apoptosis*/drug effects, Humans ; Cell Line, Tumor ; Ketoglutaric Acids/metabolism ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Aspartate Aminotransferase, Cytoplasmic/metabolism ; Aspartate Aminotransferase, Cytoplasmic/genetics ; Animals ; Promoter Regions, Genetic
مستخلص: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it kills cancer cells while sparing normal cells. However, many cancers, including pancreatic ductal adenocarcinoma (PDAC), exhibit intrinsic or acquired resistance to TRAIL, and the molecular mechanisms underlying TRAIL resistance in cancers, particularly in PDAC, remain unclear. In this study, we demonstrated that glutamine (Gln) endows PDAC cells with resistance to TRAIL through KDM4C-mediated epigenetic regulation of cFLIP. Inhibition of glutaminolysis significantly reduced the cFLIP level, leading to TRAIL-mediated formation of death-inducing signaling complexes. Overexpression of cFLIP dramatically rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Alpha-Ketoglutarate (aKG) supplementation significantly reversed the decrease in the cFLIP level induced by glutaminolysis inhibition and rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Knockdown of glutamic-oxaloacetic transaminase 2, which facilitates the conversion of oxaloacetate and glutamate into aspartate and aKG, decreased aKG production and the cFLIP level and activated TRAIL-induced apoptosis. AKG-mediated epigenetic regulation was necessary for maintaining a high level of cFLIP. Glutaminolysis inhibition increased the abundance of H3K9me3 in the cFLIP promoter, indicating that Gln-derived aKG production is important for Jumonji-domain histone demethylase (JHDM)-mediated cFLIP regulation. The JHDM KDM4C regulated cFLIP expression by binding to its promoter, and KDM4C knockdown sensitized PDAC cells to TRAIL-induced apoptosis. The present findings suggest that Gln-derived aKG production is required for KDM4C-mediated epigenetic regulation of cFLIP, which leads to resistance to TRAIL.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 2022R1A2C1007303 National Research Foundation of Korea (NRF); 2018R1A5A2020732 National Research Foundation of Korea (NRF); 2019IPO869 Asan Institute for Life Sciences, Asan Medical Center; 2021IL0003 Asan Institute for Life Sciences, Asan Medical Center; 2022IL0001 Asan Institute for Life Sciences, Asan Medical Center
المشرفين على المادة: 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
0 (TNF-Related Apoptosis-Inducing Ligand)
0RH81L854J (Glutamine)
EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
0 (KDM4C protein, human)
0 (Ketoglutaric Acids)
EC 2.6.1.- (Aspartate Aminotransferase, Cytoplasmic)
EC 2.6.1.- (GOT1 protein, human)
0 (CFLAR protein, human)
0 (TNFSF10 protein, human)
تواريخ الأحداث: Date Created: 20240429 Date Completed: 20240429 Latest Revision: 20240502
رمز التحديث: 20240502
مُعرف محوري في PubMed: PMC11058808
DOI: 10.1038/s12276-024-01231-0
PMID: 38684915
قاعدة البيانات: MEDLINE
الوصف
تدمد:2092-6413
DOI:10.1038/s12276-024-01231-0