Background
Leukemia threatens so many lives around the world. Dihydroartemisinin (DHA), as a typical derivative of artemisinin (ART), can efficiently inhibit leukemia, but the controversial mechanisms are still controversial. Many reports showed that tumor cells acquire energy through the glycolysis pathway, pyruvate kinase M2 (PKM2) plays a crucial role in regulating glycolysis. However, it is unclear whether PKM2 or other key molecules are involved in DHA induced cytotoxicity in leukemia cells. Thus, this paper systematically investigated the anticancer effect and mechanism of DHA on human chronic myeloid leukemia K562 cells.
Conclusion
The present study implicated that DHA inhibits leukemia cell proliferation by regulating glycolysis and metabolism, which mediated by downregulating PKM2 and GLUT1 expression. Our finding might enrich the artemisinins' antitumor mechanisms.
Methods
In vitro, cytotoxicity was detected with CCK-8. Glucose uptake, lactate production and pyruvate kinase activity were investigated to evaluate the effect of DHA on K562 cells. To elucidate the cellular metabolism alterations induced by DHA, the extracellular acidification rate was assessed using Seahorse XF96 extracellular flux analyzer. Immunofluorescence, real-time PCR, and Western blotting were used to investigate the molecular mechanism.
Results
We found that DHA prevented cell proliferation in K562 cells through inhibiting aerobic glycolysis. Lactate product and glucose uptake were inhibited after DHA treatment. Results showed that DHA modulates glucose uptake through downregulating glucose transporter 1 (GLUT1) in both gene and protein levels. The cytotoxicity of DHA on K562 cells was significantly reversed by PKM2 agonist DASA-58. Pyruvate kinase activity was significantly reduced after DHA treatment, decreased expression of PKM2 was confirmed in situ.