谷氨酰胺分解
缺氧(环境)
胰腺癌
癌症研究
谷氨酰胺
癌细胞
肿瘤微环境
肿瘤缺氧
氧化磷酸化
生物
癌症
化学
医学
内科学
生物化学
放射治疗
氧气
氨基酸
有机化学
肿瘤细胞
作者
Seung Joon Park,Hee Chan Yoo,Eunyong Ahn,Enzhi Luo,Yeabeen Kim,Yulseung Sung,Ya Chun Yu,Kibum Kim,Do Sik Min,Hee-Seung Lee,Geum‐Sook Hwang,Tae-Jin Ahn,Jong Myung Choi,Seungmin Bang,Jung Min Han
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-01-03
卷期号:83 (5): 735-752
被引量:6
标识
DOI:10.1158/0008-5472.can-22-2045
摘要
Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix component-based in vitro three-dimensional cell printing model with patient-derived PDAC cells that recapitulate the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared with chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.Increased glutaminolysis induces hypoxia via oxidative phosphorylation-mediated oxygen consumption and drives chemoresistance in pancreatic cancer, revealing a potential therapeutic strategy of combining glutaminolysis inhibition and chemotherapy to overcome resistance.
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