Dihydroartemisinin Regulates Self-Renewal of Human Melanoma-Initiating Cells by Targeting PKM2/LDHA-Related Glycolysis

Objectives: Melanoma-initiating cells (MICs), a group of cells with stem cell-like self-renewal ability, play a vital role in melanoma progression. They are energized by PKM2/LDHA-related glycolysis. Dihydroartemisin (DHA), a derivative of the antimalarial drug artemisinin, reportedly has a potential role in glycolysis regulation. The aim of this study was to detect the regulation of self-renewal of MICs by DHA through PKM2/LDHA-related glycolysis. Methods: The cell viability of melanoma cells following DHA treatment in vitro was measured by MTS. Cell cycle were detected by Flow cytometry. And DHA treatment in vivo was measured by Nude mouse xenograft assay. MICs selfrenewal was detected by stem cell related spheres culture and assays. Results: DHA inhibits the proliferation of melanoma cells and blocks the cell cycle process. Importantly, it suppresses the selfrenewal of MICs. Furthermore, DHA reduces ATP production and downregulate PKM2 and LDHA activities without regulating the expression of the PKM2 and LDHA proteins in melanoma cells. Moreover, DHA covalently binds to the protein skeleton of PKM2 and LDHA through its sesquiterpene lactone structure and downregulates glucose metabolism in melanoma cells. Conclusion: These findings revealed that DHA regulates self-renewal of human MICs by targeting PKM2/LDHA-related glycolysis.