Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China.
Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China.
Acta Pharmacol Sin. 2021 Sep;42(9):1472-1485. doi: 10.1038/s41401-020-00572-6. Epub 2020 Dec 10.
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·d, 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.
雷公藤红素是一种从传统中药雷公藤中提取的三萜类化合物，具有潜在的抗癌活性。本研究探讨了雷公藤红素对透明细胞肾细胞癌（ccRCC）的抗癌作用及其机制。我们利用癌症基因组图谱（TCGA）数据库和基因型组织表达（GTEx）数据库进行了生物信息学分析，结果显示 ccRCC 组织中肝 X 受体α（LXRα）和三磷酸腺苷结合盒转运体 A1（ABCA1）的 mRNA 水平明显低于相邻正常组织。这一结果通过对 4 个 ccRCC 临床标本的免疫印迹分析得到了证实，结果显示 LXRα和 ABCA1 的蛋白表达下调。在一组 ccRCC 细胞系（786-O、A498、SN12C 和 OS-RC-2）中也得到了类似的结果。在 786-O 和 SN12C 细胞中，雷公藤红素（0.25-2.0 μM）浓度依赖性地抑制细胞增殖、迁移和侵袭以及上皮间质转化（EMT）过程。此外，我们证明雷公藤红素通过减少脂质积累抑制 786-O 细胞的侵袭；雷公藤红素浓度依赖性地促进自噬以减少脂质储存。此外，我们揭示了雷公藤红素通过诱导溶酶体脂滴分解来显著激活 LXRα 信号通路，从而减少 786-O 细胞中的脂滴。最后，雷公藤红素通过 ABCA1 促进 786-O 细胞中的胆固醇外排。在高脂肪饮食促进的 ccRCC 细胞系 786-O 异种移植模型中，腹腔注射（i.p.）给药雷公藤红素（0.25、0.5、1.0 mg·kg·d，连续 4 周）剂量依赖性地抑制肿瘤生长，同时肿瘤组织中 LXRα 和 ABCA1 蛋白上调。总之，本研究揭示了雷公藤红素通过激活 LXRα在 ccRCC 中触发溶酶体脂滴分解，促进 ABCA1 介导的胆固醇外排，抑制 EMT 进展，最终抑制细胞增殖、迁移和侵袭以及肿瘤生长。因此，我们的研究提供了证据表明雷公藤红素可以作为一种基于脂质代谢的抗癌治疗方法。
