title: Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy.
abstract: Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species (ROS) such as radiation. Here, we evaluated the dependence of pancreatic cancer stem cells (PCSCs) on this non-canonical glutamine metabolism pathway and researched whether inhibiting this pathway can enhance radiosensitivity of PCSCs. We showed that glutamine deprivation significantly inhibited self-renewal, decreased expression of stemness-related genes, increased intracellular ROS, and induced apoptosis in PCSCs. These effects were countered by oxaloacetate, but not α-ketoglutarate. Knockdown of glutamic-oxaloacetic transaminase dramatically impaired PCSCs properties, while glutamate dehydrogenase knockdown had a limited effect, suggesting a dependence of PCSCs on non-canonical glutamine metabolism. Additionally, glutamine deprivation significantly increased radiation-induced ROS and sensitized PCSCs to fractionated radiation. Moreover, transaminase inhibitors effectively enhanced ROS generation, promoted radiation sensitivity, and attenuated tumor growth in nude mice following radiation exposure. Our findings reveal that inhibiting the non-canonical pathway of glutamine metabolism enhances the PCSC radiosensitivity and may be an effective adjunct in cancer radiotherapy.
authors.affiliation: Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Doudou
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ruiwan
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Department of General Surgery, Guangdong General Hospital, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Department of General Surgery, Guangdong General Hospital, Guangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Quanbo
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Pediatric Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Rufu
authors.initials: R
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D005434:Flow Cytometry; D005720:Gamma Rays / Q000009:adverse effects*; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005973:Glutamine; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases
keywords: cancer stem cells; glutamine metabolism; pancreatic ductal adenocarcinoma; radiosensitivity; reactive oxygen species