Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
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Doudou Li1,7,*, Zhiqiang Fu2,7,*, Ruiwan Chen3,*, Xiaohui Zhao4,7, Yu Zhou2,5,7, Bing Zeng2, Min Yu2,5, Quanbo Zhou2, Qing Lin2, Wenchao Gao2,7, Huilin Ye2,7, Jiajia Zhou6, Zhihua Li4, Yimin Liu1,7, Rufu Chen2,7
1Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
2Department of Hepato-Pancreato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
3Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
4Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
5Department of General Surgery, Guangdong General Hospital, Guangzhou, China
6Department of Pediatric Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
7Key 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
*These authors have contributed equally to this work
Rufu Chen, e-mail: email@example.com
Zhihua Li, e-mail: firstname.lastname@example.org
Yimin Liu, e-mail: email@example.com
Keywords: pancreatic ductal adenocarcinoma, glutamine metabolism, cancer stem cells, reactive oxygen species, radiosensitivity
Received: January 24, 2015 Accepted: August 21, 2015 Published: September 03, 2015
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.
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