Zinc regulates primary ovarian tumor growth and metastasis through the epithelial to mesenchymal transition

Background: The trace element zinc plays an indispensable role in human health and diseases including cancer due to its antioxidant properties. While zinc supplements have been used for cancer prevention, zinc is also a risk factor for cancer development. It is still unclear how zinc plays a role in ovarian cancer. Methods: To understand how zinc contributes to ovarian tumor growth and metastasis, we examined whether zinc contributes to tumor metastasis by regulating epithelial to mesenchymal transition (EMT) using ovarian cancer cells in vitro. Cell migration and invasion were examined using transwell plates and EMT markers were examined using Western blot. Primary ovarian tumor growth and metastasis were assessed using orthotopic ovarian cancer mouse models in vivo. Results: Zinc promoted EMT, while TPEN (N, N, N', N'-tetrakis-(2-pyridylmethyl)-ethylenediamine), a membrane-permeable selective zinc chelator, inhibited EMT in a dose dependent manner in ovarian cancer cells. Moreover, zinc promoted ovarian cancer cell migration and invasion, while TPEN inhibited cell migration and invasion. Zinc activated expression of the metal response transcriptional factor-1 (MTF-1), while TPEN inhibited MTF-1 expression in a dose dependent manner. Knockout of MTF-1 inhibited zinc-induced cell migration, invasion and augmented the inhibitory effect of TPEN on cell migration and invasion. Loss of MTF-1 attenuated zinc-induced ERK1/2 and AKT activation and augmented the effect of TPEN in attenuating the ERK1/2 and AKT pathways. TPEN effectively inhibited primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse model by suppressing EMT. Conclusion: zinc contributes to ovarian tumor metastasis by promoting EMT through a MTF-1 dependent pathway. Zinc depletion by TPEN may be a novel approach for ovarian cancer therapy by inhibiting EMT and attenuating the ERK1/2 and AKT pathways.