Park Seung Joon, Yoo Hee Chan, Ahn Eunyong, Luo Enzhi, Kim Yeabeen, Sung Yulseung, Yu Ya Chun, Kim Kibum, Min Do Sik, Lee Hee Seung, Hwang Geum-Sook, Ahn TaeJin, Choi Junjeong, Bang Seungmin, Han Jung Min
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, South Korea.
Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, South Korea.
Cancer Res. 2023 Mar 2;83(5):735-752. doi: 10.1158/0008-5472.CAN-22-2045.
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.
胰腺导管腺癌（PDAC）表现出严重缺氧，这与化疗耐药性及患者较差的预后相关。据报道，缺氧会诱导癌细胞发生代谢重编程。然而，代谢重编程是否导致缺氧尚不清楚。在此，我们证实谷氨酰胺分解增加是诱导PDAC细胞缺氧从而产生化疗耐药性的一种基本机制。基于细胞外基质成分的体外三维细胞打印模型，使用患者来源的PDAC细胞并模拟PDAC肿瘤中的缺氧状态，结果显示，与化疗敏感的PDAC细胞相比，化疗耐药的PDAC细胞表现出明显增强的谷氨酰胺分解。增加的谷氨酰胺代谢通量通过线粒体氧化磷酸化（OXPHOS）提高了耗氧率，促进了缺氧及缺氧诱导的化疗耐药性。靶向谷氨酰胺分解可缓解缺氧，并在体外和体内提高化疗疗效。这项研究表明，靶向谷氨酰胺分解 - OXPHOS - 缺氧轴是治疗化疗耐药性PDAC患者的一种新的治疗靶点。
谷氨酰胺分解增加通过氧化磷酸化介导的耗氧诱导缺氧，并驱动胰腺癌的化疗耐药性，揭示了一种联合抑制谷氨酰胺分解和化疗以克服耐药性的潜在治疗策略。
