Enhanced Glutaminolysis Drives Hypoxia-Induced Chemoresistance in Pancreatic Cancer

Abstract

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 (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to 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.

Hypoxia expedites the progression of papillary thyroid carcinoma by promoting the CPT1A‐mediated fatty acid oxidative pathway

“…Hypoxia is an important factor in promoting thyroid cancer progression and metastasis (Bao & Wong, 2021). Indeed, solid tumors often grow in a hypoxic environment and thus their biological properties are already altered (Chen & Lou, 2017; Chiu et al, 2017; Park et al, 2023). In this state, hypoxia‐inducible factors play important roles, and the upregulation of HIF‐1α leads to a series of changes, including the promotion of erythropoiesis, the increase of oxygen supply to tumor tissues, the promotion of intra‐tumor angiogenesis, the mediation of glycolytic function in the state of ischemia and hypoxia, and the inhibition of apoptosis (Schödel et al, 2016).…”

PET Imaging of Metabolism, Perfusion, and Hypoxia

“…Furthermore, the enhanced glutaminolysis in cancer is associated with hypoxia and can influence the drug resistance of cancer. 16,17 Therefore, the metabolic profiling of various tumor microenvironments is very important in understanding tumor biology.…”

“…These factors promote a shift toward glycolysis and away from oxidative phosphorylation, further enhancing the Warburg effect. Furthermore, the enhanced glutaminolysis in cancer is associated with hypoxia and can influence the drug resistance of cancer 16,17 . Therefore, the metabolic profiling of various tumor microenvironments is very important in understanding tumor biology.…”

KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression

“…KRAS mutation promoting glutamine metabolism in pancreatic cancer can also be studied in relation to surrounding stromal cells or associated supporting cells. Glutamine addiction in pancreatic cancer is also a major cause of its chemoresistance ( Ganguly et al, 2022 ; Park et al, 2023 ). A great deal of research is still needed on glutamine metabolism in pancreatic cancer, which is expected to provide efficient targets for the clinical treatment of pancreatic cancer.…”