Li Doudou, Fu Zhiqiang, Chen Ruiwan, Zhao Xiaohui, Zhou Yu, Zeng Bing, Yu Min, Zhou Quanbo, Lin Qing, Gao Wenchao, Ye Huilin, Zhou Jiajia, Li Zhihua, Liu Yimin, Chen Rufu
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.
Oncotarget. 2015 Oct 13;6(31):31151-63. doi: 10.18632/oncotarget.5150.
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.
胰腺导管腺癌（PDAC）细胞利用一种新型非经典谷氨酰胺代谢途径，该途径对肿瘤生长和氧化还原平衡至关重要。抑制PDAC中的这种代谢途径可能与增加细胞内活性氧（ROS）的疗法（如放疗）产生协同作用。在此，我们评估了胰腺癌干细胞（PCSCs）对这种非经典谷氨酰胺代谢途径的依赖性，并研究了抑制该途径是否能增强PCSCs的放射敏感性。我们发现，谷氨酰胺剥夺显著抑制了PCSCs的自我更新，降低了干性相关基因的表达，增加了细胞内ROS，并诱导了PCSCs的凋亡。草酰乙酸可抵消这些作用，但α-酮戊二酸则不能。谷氨酸草酰乙酸转氨酶的敲低显著损害了PCSCs的特性，而谷氨酸脱氢酶的敲低作用有限，这表明PCSCs依赖于非经典谷氨酰胺代谢。此外，谷氨酰胺剥夺显著增加了辐射诱导的ROS，并使PCSCs对分次放疗敏感。此外，转氨酶抑制剂可有效增强ROS的产生，提高辐射敏感性，并在裸鼠辐射后减弱肿瘤生长。我们的研究结果表明，抑制谷氨酰胺代谢的非经典途径可增强PCSCs的放射敏感性，可能是癌症放疗的一种有效辅助手段。
