Succinate dehydrogenase 5 regulates lung cancer metastasis by reprogramming glucose metabolism

BACKGROUND: Lung cancer is the leading cause of cancer-related death globally, with many of these patients also suffering from diabetes. Previous studies have shown that diabetes may contribute to cancer progression through hyperglycemia. However, the underlying mechanism remains largely unknown. This study aimed to investigate the role of succinate dehydrogenase 5 (SDH5), an enzyme required for assembling respiratory complex II in lung cancer patients with diabetes. METHODS: The expression levels of SDH5 in patient plasma and tissue were determined by RT-qPCR. Western blotting, immunofluorescence (IF), and immunohistology (IHC) were used to examine protein expression. Migration and invasion assays were performed using Transwell assays. Reactive oxygen species (ROS) production was detected by flow cytometry. Bioluminescent imaging (BLI) was used to detect tumor metastasis in a lung orthotopic mouse model. RESULTS: In samples from non-small cell lung cancer (NSCLC) patients with diabetes, SDH5 mRNA levels were significantly lower in both plasma and tissue among later stage patients. TCGA data showed that low SDH5 expression was correlated with a higher expression of genes involved in glycolysis and metastasis. In vitro, high glucose conditions alone induced epithelial-to-mesenchymal transition (EMT) in cells, an effect that was further reinforced by SDH5 depletion. Additionally, depleting SDH5 promoted glucose consumption and lactate production. The underlying mechanism indicates that depleting SDH5 stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), which is dependent on ROS production. In vivo, SDH5-deficient tumor-bearing mice had multiple organ metastases, which is consistent with the in vitro findings. CONCLUSIONS: Our findings suggest that SDH5 deficiency activates HIF-1α to promote EMT under high glucose conditions and represents a predictive marker for NSCLC patients with diabetes.