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

Objective: Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb, Tripterygium wilfordii . This study aimed to provide a scientific basis for the rational development and use of celastrol in breast cancer. Methods: 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, BaX, increased, the level of the anti-apoptotic protein, 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 MS (Mass Spectrometry) data indicated a relationship between HSDL2 and the MAPK signaling pathway. We also found that the expression of HSDL2 was directly related to the degree of ERK phosphorylation. Conclusions: Celastrol may promote apoptosis by suppressing the HSDL2/ MAPK/ERK signaling pathway.