期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 150, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2022.113063
关键词
Pimozide; Warburg effect; PI3K; Akt; MDM2; P53; PKM2; Breast cancer
资金
- Korean Food Research Project [2017029]
- National Natural Science Foundation of China [61671098, 31560312]
In this study, it was found that Pimozide inhibits the Warburg effect in breast cancer cells by hindering glucose uptake, ATP production, and lactate production. Mechanistically, Pimozide mediates the p53 signaling pathway through PI3K/Akt/MDM2, thereby suppressing the expression of PKM2 and reprogramming glucose metabolism in breast cancer cells.
The Warburg effect is a promising target for the diagnosis and treatment of cancer, referring to the ability of cancer cells to generate energy through high levels of glycolysis even in the presence of oxygen, allowing them to grow and proliferate rapidly. The antipsychotic Pimozide has strong anti-breast cancer effects both in vivo and in vitro, whether Pimozide has an inhibitory effect on aerobic glycolysis has not been elucidated. In this study, Pimozide inhibited the Warburg effect of breast cancer cells by hindering glucose uptake, ATP level and lactate production; reducing the extracellular acidification rate (ECAR); suppressing the expression of PKM2, a ratelimiting enzyme in glycolysis. Intriguingly, Pimozide was significantly involved in reprogramming glucose metabolism in breast cancer cells through a p53-dependent manner. Mechanistic studies demonstrated Pimozide increased the expression of p53 through inhibition of the PI3K/Akt/MDM2 signaling pathway, which in turn downregulated the expression of PKM2. In sum, our results suggest that Pimozide mediates the p53 signaling pathway through PI3K/AKT/MDM2 to inhibit the Warburg effect and breast cancer growth, and it may be a potential aerobic glycolysis inhibitor for the treatment of breast cancer.
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