Celastrol is a
triterpene derived from the
traditional Chinese medicine Tripterygium wilfordii Hook f, which displays potential anticancer activity. In the present study, we investigated the anticancer effects of
celastrol against
clear cell renal cell carcinoma (ccRCC) and the underlying mechanisms. Using
Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx) database we conducted a bioinformatics analysis, which showed that the
mRNA levels of
liver-X receptors α (LXRα) and
ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues. This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens, which showed that the
protein expression of LXRα and ABCA1 was downregulated. Similar results were obtained in a panel of ccRCC cell lines (786-O, A498, SN12C, and OS-RC-2). In 786-O and SN12C cells, treatment with
celastrol (0.25-2.0 μM) concentration-dependently inhibited the cell proliferation, migration, and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, we demonstrated that
celastrol inhibited the invasion of 786-O cells through reducing
lipid accumulation;
celastrol concentration-dependently promoted autophagy to reduce
lipid storage. Moreover, we revealed that
celastrol dramatically activated LXRα signaling, and degraded lipid droplets by inducing lipophagy in 786-O cells. Finally,
celastrol promoted
cholesterol efflux from 786-O cells via ABCA1. In high-fat diet-promoted ccRCC cell line 786-O xenograft model, administration of
celastrol (0.25, 0.5, 1.0 mg·kg-1·d-1, for 4 weeks, i.p.) dose-dependently inhibited the
tumor growth with upregulated LXRα and
ABCA1 protein in
tumor tissue. In conclusion, this study reveals that
celastrol triggers lipophagy in ccRCC by activating LXRα, promotes ABCA1-mediated
cholesterol efflux, suppresses EMT progress, and ultimately inhibits cell proliferation, migration, and invasion as well as
tumor growth. Thus, our study provides evidence that
celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.