Celastrol promotes apoptosis of breast cancer MDA-MB-231 cells by targeting HSDL2

Abstract

Objective: Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb, Tripterygium wilfordii. This study aims to provide a scientific basis for the rational development and use of celastrol in breast cancer.
Method: A quantitative chemical biology approach was used to investigate the protein targets and molecular mechanisms of celastrol in breast cancer cells.
Results: Low-concentration celastrol exerted an anti-tumor effect by directly binding to hydroxysteroid dehydrogenase-like 2 (HSDL2) and inhibiting its expression. Moreover, the expression of the pro-apoptotic protein, Bcl-2-associated X (BaX), increased, the level of the anti-apoptotic protein, B-cell lymphoma-2 (Bcl-2), decreased, and the rate of apoptosis increased. After the transfection of cells with si-HSDL2, the apoptosis rate was similar to that observed after the administration of celastrol. However, apoptosis was reversed by the overexpression of HSDL2. Furthermore, our mass spectrometry (MS) data indicated a relationship between HSDL2 and the mitogen-activated protein kinase (MAPK) signaling pathway. We also found that the expression of HSDL2 was directly related to the degree of extracellular signal-regulated kinase (ERK) phosphorylation.
Conclusion: Celastrol may promote apoptosis by suppressing the HSDL2/MAPK/ERK signaling pathway.

Keywords

Activity-based protein profiling / Apoptosis / Celastrol / HSDL2

Conflict of interest statement

The authors declare no conflict of interest.

Funding

The following financing sources are acknowledged for their assistance: the National Key Research and Development Program of China (2020YFA0908000 and 2022YFC2303600), the National Natural Science Foundation of China (81903866 and 82274182), and the Central Public Welfare Research Institutes (ZZ13-YQ-105; ZZ15-YQ-065; ZZ14-YQ-058).

Author contributions

The experiments were created by Jigang Wang and Yongping Zhu, who also oversaw the initiative. The main experiments, paper writing, and data analysis were done by Liu Li and Yanqing Liu. Shujie Zhang, Liting Xu, Ziyue Zhang, Minghong Zhao, and Qixin Wang helped with in vitro experiments. Liwei Gu, Dandan Liu, and Yuqing Meng revised the manuscript. Junzhe Zhang and Ying Zhang performed mass spectrometry experiments. The final manuscript was reviewed and approved by all authors.

Ethical approval of studies and informed consent

Written informed consent for publication of this paper was obtained from the Gannan Medical University of Arts and Science and all authors.

Acknowledgments

We appreciate the contributions made to this continually developing area of celastrol study by our coworkers, colleagues, and laboratory staff.

Data availability statement

All data associated with this study are present in the paper or the Supplementary Materials.

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Acupuncture and Herbal Medicine