Seung Joon Park1,2, Hee Chan Yoo2, Eunyong Ahn3, Enzhi Luo2, Yeabeen Kim4, Yulseung Sung2, Ya Chun Yu2, Kibum Kim2, Do Sik Min2, Hee Seung Lee5, Geum-Sook Hwang3, TaeJin Ahn4, Junjeong Choi2, Seungmin Bang5, and Jung Min Han1,2,6
1Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, South Korea.
2Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, South Korea.
3Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, South Korea.
4Department of Life Science, Handong Global University, Pohang, South Korea.
5Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
6POSTECH Biotech Center, Pohang University of Science and Technology, Pohang, South Korea.
S.J. Park and H.C. Yoo contributed equally as co-authors of this article.
Corresponding Authors: Seungmin Bang, Jung Min Han
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.