Cyperotundone Regulates Polo-like Kinase 1-mediated Glycolysis to Inhibit the Proliferation of Breast Cancer Cells
Xiaoyu Liu, Xiang Song, Jingwei Li, Zhiyong YuIntroduction:
Cyperotundone (CYT), a vital component of Cyperus rotundus L., is known to suppress tumor growth effectively. This investigation was performed to reveal the antibreast cancer(BC) effect of CYT and its mechanism.
Methods:
CCK-8 assay, colony formation, cell cycle/apoptosis assays, and subcutaneous tumor model were used to investigate the anticancer effects of CYT. RNA sequencing was used to predict the targets of CYT, which were then verified by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking. The pan-cancer analysis on PLK1 was excavated by the comprehensive use of datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx). Western blotting, immunohistochemical staining (IHC), and RT-qPCR were used to determine protein and gene levels. Pyruvate and lactate production assays were used to represent the glycolysis level.
Results:
CYT inhibited the proliferation of BC cells, as well as causing apoptosis and blocking the cell cycle. In vivo, CYT decreased tumor regression without obvious toxicity. PLK1 was identified as a key target of CYT. High PLK1 expression was associated with early diagnostic value and poor survival of BC. Of note, PLK1 is positively correlated with glycolysis. CYT can inhibit the key proteins of glycolysis and production of metabolites through the PTEN/AKT pathway in BC cells. In the rescue experiments, CYT significantly inhibited the overexpression of PLK1-induced elevation of glycolysis level
Discussion:
This is the first study to reveal the correlation between PLK1 and glycolysis and the regulation of glycolysis by PLK1 in TNBC cells. Although PLK1 was identified as a target of CYT, the research on how CYT exerts its anti-BC effect through PLK1 is still insufficient. Other molecular pathways involved in CYT action, how disruption of glycolytic pathways contributes to its anticancer effects, and its potential compensatory mechanisms in cancer cells are needed to explore.
Conclusion:
CYT is a potent PLK1 inhibitor that has an anticancer effect in BC cells by decreasing glycolytic function.