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 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.