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

Abstract

BackgroundEpithelial 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.MethodsThe 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.ResultsThe 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.ConclusionKnowledge 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.

Iron and copper complexes with antioxidant activity as inhibitors of the metastatic potential of glioma cells

“…Since an increase in ROS had been previously implicated in EMT induction in different cells, [18][19][20][21] we hypothesized that the reduction in ROS levels induced by the compounds could be leading to changes in the metastatic ability of H4 cells. The effect of FeL and CuL on the migration of H4 cells was thus investigated by the transwell migration assay.…”

“…17 Interestingly, the EMT process seems to be connected to cellular ROS levels and different metals have been shown to induce EMT in different cancers through a ROSdependent mechanism. [18][19][20][21] As such, modulation of ROS levels in cancer cells has been put forth as another promising strategy to tackle the problem of local invasiveness and metastization of cancer. 22 One possible strategy to modulate the levels of cellular ROS, and, consequently, the cancer cells metastatic ability, is the use of metal-based compounds that mimic the superoxide dismutase (SOD) and catalase (CAT) enzymes, important cellular antioxidant proteins that are responsible for maintaining the cellular redox balance.…”

Redox regulation in tumor cell epithelial–mesenchymal transition: molecular basis and therapeutic strategy

“… 150 In lung cancer cells, zinc treatment induces EMT by increasing O 2 •− levels, which can be attenuated by MnTBAP, a specific superoxide inhibitor. 151 Moreover, the zinc transporter ZIP10 (SLC39A10) has been reported to stimulate EMT by inactivating GSK-3β and downregulating E-cadherin. 152 Another zinc transporter, LIVI, has also been identified as an important regulator of the nuclear translocation of Snail and STAT-mediated EMT.…”

A Summary of In Vitro and In Vivo Studies Evaluating the Impact of E-Cigarette Exposure on Living Organisms and the Environment

“…Trace metals can accumulate in smokers following prolonged use, thus resulting in adverse health effects. Studies suggest a close relationship between exposure to aluminum [47], arsenic [48], cadmium [49], chromium [50], copper [51], manganese [52], nickel [53], lead [54] and zinc [55] and predisposition to the following respective lung pathologies, diffuse parenchymal lung disease, impaired lung function, lung cancer, chronic lung inflammation and injury, pulmonary inflammation, occupational asthma, respiratory tract cancer, higher frequency of respiratory symptoms, altered regulation of the epithelial-mesenchymal transition (EMT) process.…”