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Selective effects of ionophores targeting the Golgi apparatus in the epithelial-to-mesenchymal transition

Introduction: The epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis, drug resistance and could give rise to cells with properties similar to cancer stem cells (CSCs). Targeting the EMT program to selectively eliminate CSCs is a promising strategy to improve cancer therapy. A recent study using an in vitro model that recapitulates EMT in human prostate cancer identified a monovalent ionophore and GA disturbing agent monensin (Mon) as an effective anticancer drug that is selective against EMT-like cells. Another K+/H+ ionophore salinomycin (Sal) was previously identified as a selective inhibitor of CSC-like cells, but the mechanism of its action is still not fully understood. Given that Mon and Sal are both monovalent cation ionophores and show potent anticancer effects, here we consider the possibility that both of them mediate their inhibitory effects on EMT and CSC by disrupting GA. Objectives: To elucidate the effects of Sal and Mon on GA and test the possibility that the disruption of Golgi architecture and function mediates their effects on EMT and CSC. Materials & methods: We used a breast CSC model, established by experimental induction of EMT in immortalized human mammary epithelial cells (HMLE). We performed global gene expression profiling by RNA- Seq, western blotting, flow cytometry and confocal microscopy, as well as analysed the N-Glycome on secreted proteins. Results: We demonstrated that both Sal and Mon showed selective cytotoxic effects against cells exhibiting EMT phenotypes. Sal induced expression of Golgi-related genes and, similarly to Mon, lead to marked changes in Golgi morphology, particularly in EMT cells. Both ionophores affected protein post-translational modifications including protein processing and glycosylation that take place inside GA. Conclusions: Our study demonstrates, for the first time, that Sal is a GA disturbing agent and identifies an increased sensitivity to GA disruption as a novel vulnerability of EMT cells. Based on our results, we propose that targeting GA could be a novel therapeutic approach for metastatic cancer patients. However, further studies are needed to gain better insight into the links between GA morphology and function and EMT that could be specifically targeted in cancer.

ionophores ; Golgi apparatus ; epithelial-to-mesenchymal transition ; cancer therapy

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