Celastrol inhibits the proliferation and migration of MCF-7 cells through the leptin-triggered PI3K/AKT pathway

Graphical abstract

Abstract

Leptin is the pivotal modulator in the onset and progression of breast cancer and obesity. Celastrol, which is extracted from the roots of Tripterygium wilfordi plants, exerts various anticancer bioactivities and has recently emerged as a candidate to treat obesity by improving leptin sensitivity. However, the relationship between leptin and celastrol in the treatment of breast cancer is unknown. Here, the growth and migration of MCF-7 cells induced by leptin were tested to demonstrate the antineoplastic activity of celastrol. Transcriptomic analysis and western blotting were conducted to explore the biological roles of leptin in treating breast cancer with celastrol. The present findings showed that celastrol remarkably reversed leptin-triggered cell proliferation and migration in MCF-7 cells. Fifty-two mRNAs with fivefold higher counts and 149 mRNAs with fivefold lower counts were identified in the celastrol-treated MCF-7 cells. According to the GO and KEGG analyses, the effects of celastrol on MCF-7 cells forced lipid metabolism and the endocrine system. Moreover, leptin treatment induced phosphorylation of leptin receptor and PI3K/AKT in MCF-7 cells, whereas pretreatment with celastrol partly abrogated leptin activation. The binding of celastrol to the leptin receptor was also confirmed by molecular docking. The antitumor effect of celastrol is proposed to be mediated by its binding to the leptin receptor and controlled downregulation of the PI3K/AKT pathway.