Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial-Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis

Background: Tumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O-2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1 alpha). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized. Methods: We employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1 alpha-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice. Results: HBO suppressed hypoxia-induced HIF-1 alpha expression and downstream HIF-1 alpha signaling in NSCLC cells. One HIF-1 alpha-induced glucose metabolism gene-Phosphofructokinase, Platelet (PFKP)-most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1 alpha downregulation. HBO's suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1 alpha/PFKP axis. In vivo, HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner. Conclusions: HBO's repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1 alpha downregulation. HIF-1 alpha's target gene PFKP functions as a central mediator of HBO's effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors.

Automated summary

The study showed that HBO suppresses hypoxia-induced HIF-1 alpha expression and downstream signaling in NSCLC cells, leading to inhibition of the Warburg effect, hyperproliferation, and epithelial-to-mesenchymal transition. The HIF-1 alpha target gene PFKP plays a central role in mediating HBO's effects and may be a potential metabolic vulnerability in NSCLC tumors.