Anthraquinone modifier KA-4c triggers endoplasmic reticulum stress and targets ATF6 against breast cancer cells / 中国药理学通报

ABSTRACT

Aim To explore the mechanism of the effect of anthraquinone modifier KA-4c on breast cancer cells, and determine its action target by drug affinity reaction target stability technique (DARTS). Methods The cell viability was detected by MTT method. The effect of KA-4c on the morphology of breast cancer cells was studied by HE staining, ER-Tracker Red and electron microscope. The apoptosis rate of breast cancer cells induced by KA-4c was detected by flow cytometry. The expression of apoptotic protein was detected by Western blotting. DARTS and CETSA were used to determine the target of KA-4c. Results KA-4c had the most significant inhibitory effect on the proliferation of triple negative breast cancer MDA-MB231 cells, and could cause endoplasmic reticulum and mitochondrial vacuolation to damage the cells. The apoptosis rate and the expression of apoptosis-related proteins CHOP and caspase-7 increased with the increase of KA-4c concentration. DARTS results showed that KA-4c could activate endoplasmic reticulum protein processing signaling pathway, in which KA-4c bound to ATF6 protein and was resistant to protease hydrolysis. The results of CETSA experiments showed that KA-4c could enhance the expression of ATF6 protein in a concentration-dependent manner. Conclusions KA-4 triggers endoplasmic reticulum stress to induce apoptosis in breast cancer cells. ATF6 may be one of the targets of KA-4c.