Enhanced Glutaminolysis Drives Hypoxia-Induced Chemoresistance in Pancreatic Cancer.

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. SIGNIFICANCE: 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.

Particulate Matter Promotes Melanin Production through Endoplasmic Reticulum Stress‒Mediated IRE1α Signaling.

Particulate matter (PM) is believed to be related to cardiovascular and respiratory diseases. The skin is also known to be affected by PM exposure as a result of skin barrier dysfunction, cutaneous inflammation, and apoptotic cell death. Epidemiological studies have suggested that PM is related to pigment spots. Recently, diesel exhaust particles are reported to cause a tanning response mediated by oxidative stress. However, the direct effects of PM on melanogenesis and the related mechanisms have not yet been clarified. Our study showed that PM can increase melanin production in melanocyte, mouse skin, and human skin models. RNA-sequencing analyses of melanocytes revealed that the expressions of unfolded protein response molecules were increased after PM exposure. In particular, IRE1α signaling pathway, which was consistently upregulated, was related to PM-triggered melanogenesis. In addition, PM-induced melanogenesis was abrogated by an IRE1α inhibitor. Therefore, our findings corroborate previous findings in melanocytes and in mouse and human models and also illuminate the involvement of the IRE1α pathway as a mechanism of PM-induced melanogenesis.