Zinc induces epithelial to mesenchymal transition in human lung cancer H460 cells via superoxide anion-dependent mechanism

Cancer Cell Int. 2016 Jun 17;16:48. doi: 10.1186/s12935-016-0323-4. eCollection 2016.

Abstract

Background: Epithelial to mesenchymal transition (EMT) has been shown to be a crucial enhancing mechanism in the process of cancer metastasis, as it increases cancer cell capabilities to migrate, invade and survive in circulating systems. This study aimed to investigate the effect of essential element zinc on EMT characteristics in lung cancer cells.

Methods: The effect of zinc on EMT was evaluated by determining the EMT behaviors using migration, invasion and colony formation assay. EMT markers were examined by western blot analysis. Reactive oxygen species (ROS) were detected by specific fluorescence dyes and flow cytometry. All results were analyzed by ANOVA, followed by individual comparisons with post hoc test.

Results: The present study has revealed for the first time that the zinc could induce EMT and related metastatic behaviors in lung cancer cells. Results showed that treatment of the cells with zinc resulted in the significant increase of EMT markers N-cadherin, vimentin, snail and slug and decrease of E-cadherin proteins. Zinc-treated cells exhibited the mesenchymal-like morphology and increased cancer cell motility with significant increase of activated FAK, Rac1, and RhoA. Also, tumorigenic abilities of lung cancer cells could be enhanced by zinc. Importantly, the underlying mechanism was found to be caused by the ability of zinc to generate intracellular superoxide anion. Zinc was shown to induce cellular superoxide anion generation and the up-regulation of EMT markers and the induced cell migration and invasion in zinc-treated cells could be attenuated by the treatment of MnTBAP, a specific superoxide anion inhibitor.

Conclusion: Knowledge gains from this study may highlight the roles of this important element in the regulation of EMT and cancer metastasis and fulfill the understanding in the area of cancer cell biology.

Keywords: Epithelial-to-mesenchymal transition; Lung cancer; Metastasis; Reactive oxygen species; Superoxide anion; Zinc.