Multi-omics revealed GOT1/ALDH3A1 pathway attenuated head and neck squamous cell carcinoma and increased cisplatin sensitivity through ROS induced by mitochondrial dysfunction

Current treatment options for head and neck squamous cell carcinoma (HNSCC) are limited. Aspartate aminotransaminase (GOT1) plays an important role in cancer development but its role in HNSCC remains unknown. We combined proteomics and metabolomics to identify high GOT1expression in human cancer tissues. The effects of GOT1 knockdown on cancer cell proliferation were confirmed using CCK8, wound healing assays, colony formation assays, and EdU assays. The anti-apoptotic ability of cancer cells was evaluated using TUNEL assay and flow cytometry. GOT1 knockdown caused mitochondrial dysfunction and was characterized by reduced mitochondrial membrane potential and altered expression of mitochondrial electron transport chain complexes and key transcription factors, as measured by JC-1 and qRT-PCR. Given that mitochondria are the primary source of reactive oxygen species (ROS), we assessed cellular ROS and mitochondrial superoxide levels by flow cytometry and found a significant increase. GOT1 knockdown increased the sensitivity of cells to cisplatin and decreased the volume of tumors in vivo. In summary, GOT1 knockdown inhibited proliferation and promoted apoptosis via ROS overproduction from mitochondrial dysfunction, thereby increasing cisplatin sensitivity. RNA-seq further identified aldehyde dehydrogenase 3A1 (ALDH3A1) as potentially downstream target of GOT1. These findings suggest that GOT1 knockdown may improve clinical outcomes in HNSCC.