Rapamycin antagonizes cadmium-induced breast cancer cell proliferation and metastasis through directly modulating ACSS2
Yidan Liang, Lai Yi, Ping Deng, Liting Wang, Yang Yue, Hui Wang, Tian Li, Jia Xie, Mengyan Chen, Yan Luo, Zhengping Yu, Huifeng Pi, Zhou Zhou
Abstract
Cadmium (Cd) is a carcinogen that stimulates breast cancer (BC) progression. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus that possesses a wide array of pharmacological activities, including anti-BC activity. However, the effects of rapamycin on Cd-increased BC progression and the underlying mechanism have not been fully elucidated. Here, we hypothesize that rapamycin antagonizes Cd-induced BC cell proliferation and metastasis by directly modulating ACSS2. In this study, we found that rapamycin efficiently inhibited Cd-induced proliferation, invasion and migration in MCF-7 and T47-D cells. Moreover, a surface plasmon resonance (SPR) assay confirmed that rapamycin directly binds to the ACSS2 protein with a calculated equilibrium dissociation constant (KD) of 18.3 μM. Molecular docking showed that there are three binding sites in the ACSS2 protein and that rapamycin binds at the coenzyme A (COA) binding site with a docking score of - 12.26 and a binding free energy of - 26.34 kcal/mol. More importantly, rapamycin suppresses Cd-induced BC progression by activating ACSS2. After cells were cotreated with an ACSS2 inhibitor, the effects of rapamycin were abolished. In conclusion, our findings suggest that rapamycin suppresses Cd-augmented BC progression by upregulating ACSS2, and ACSS2 may serve as a direct target of rapamycin for inhibiting xenobiotic (e.g., Cd)-mediated BC progression.