The role of nitric oxide synthase signaling pathway in the Zn-induced cellular responses in MCF-7 cells

• We examine the Zn-induced cellular responses in MCF-7 cells.
• Trace amount ZnCl2 increases NO level, but it has little effect on genetic level.
• Excess ZnCl2 decreases NO production with the release of Ca2+.
• Excess ZnCl2 further increases NO level with the activated expression of NOSs.
• Acute cytotoxicity induced by ZnCl2 is related to the NOS-mediated ROS generation.

Trace amount zinc plays key roles in biological systems, while in excessive amount it causes toxic effects. Evidence shows that there exists a crosstalk between NO and Zn apoptotic signal transduction pathway. However, the potential mechanism of Zn-induced cellular responses through the NOS signaling pathway has not been determined yet. In this research, trace amount ZnCl2 (1 nM) could induce the NO production, however it appears that this influence does not extend to genetic level in MCF-7 cells. Whereas, excess ZnCl2 (100 μM, 1 mM) could lead to a decreased NO production first with the release of Ca2+, and then induce the NO production with the transcriptional and translational activation of NOSs. The ROS generation was also induced by excess ZnCl2, causing the elF2α phosphorylation. The alleviation effect of N-acetyl-l-cysteine or l-arginine on the Zn-induced ROS generation and apoptosis suggested that Zn-induced apoptosis was associated with the NOS-mediated oxidative stress.