Targeting zinc metabolism for breast cancer inhibition in mice
The breast cancer prognosis remains challenging, with an increased zinc level reported in some breast tumor tissue. This study investigated the impact of a zinc chelator, (9-anthrylmethyl) bis(2-pyridylmethyl) amine (APA) on breast cancer cells both in vitro and in vivo. We report that APA application inhibits breast cancer cell proliferation and zinc metabolism. Our RNA-seq analysis demonstrated that APA treatment influenced cell cycle progression and division by downregulating DNA synthesis and DNA damage repair processes. Further, qPCR and western blot analyses showed that the mRNA and protein expression of cyclins were downregulated by APA application. Interestingly, the addition of zinc chloride (Zncl2) did not decrease APA toxicity but instead significantly enhanced its' effect. Furthermore, the zinc exporter, slc30a1, was upregulated after APA treatment. By using Fluozin3 staining, we detected that zinc concentration in the cytoplasm of SLC30A1 knockdown MDAMB231 cells was significantly elevated. Moreover, the reduction of slc30a1 enhanced the APA inhibitory effect on MDAMB231 cells in vitro. Finally, we found that APA combined with slc30a1 blockage significantly suppressed MDAMB231 tumor growth in a xenograft mouse model. Overall, this study suggests that APA disrupts cellular zinc metabolism. Combination with APA and slc30a1 inhibition providing a promising clinical approach for breast cancer treatment. Overall design: MDAMB231 cells were treated with DMSO or APA (40 µM) for 24 h