Hypoxanthine activates PI3K/AKT pathway and lipid metabolism, hallmarks in breast cancer metastasis.

Metastasis is the primary cause of death in women with breast cancer, which ranks among the most prevalent malignant diseases. Recently, we identified the significant metastatic role of hypoxanthine (HYP) in cancer cells. HYP is a naturally occurring purine derivative that actively participates in the synthesis of nucleic acids via the nucleotide salvage pathway. To gain a deeper insight onto the metastatic mechanism of HYP, integrated transcriptomics and metabolomics were conducted following the treatment of MCF-7 cells with HYP. HYP significantly activates PI3K/AKT pathway, a hallmark of cancer metastasis. Glycerolipid and fatty acid metabolisms are among the top-upregulated lipid metabolic pathways, while glycolysis is dysregulated. Seahorse real-time ATP rate analysis revealed a significant decrease in ATP production from the glycolysis pathway in HYP-treated cancer cells. On the other hand, genetic information processes including gene transcription and protein translation were downregulated. Collectively, our results highlight the contribution of HYP to cancer cell metastasis through the PI3K/AKT pathway. Consequently, manipulating HYP release could serve as a therapeutic target for the management of breast cancer.