Salinomycin disturbs Golgi apparatus function and specifically affects cells in epithelial-to-mesenchymal transition.

Abstract

Epithelial-to-mesenchymal transition (EMT) gives rise to cells with properties similar to cancer stem cells (CSCs). Targeting the EMT program to selectively eliminate CSCs is a promising way to improve cancer therapy. Salinomycin (Sal), a K+/H+ ionophore, was identified as highly selective towards CSC-like cells, but its mechanism of action and selectivity remains elusive. Here we show that Sal, similarly to monensin and nigericin, disturbs the function of the Golgi apparatus (GA). Sal alters the expression of GA-related genes and leads to marked changes in GA morphology, particularly in cells that underwent EMT. Moreover, GA disturbing agents severely affect post-translational modifications of proteins, including protein processing, glycosylation, and secretion. We discover that the alterations induced by GA disturbing agents specifically affect the viability of EMT cells. Collectively, our work reveals a novel vulnerability related to the EMT, suggesting an important role for the GA in the EMT, while targeting the GA represents a novel therapeutic approach against CSCs.