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United States Department of Agriculture

Agricultural Research Service

Research Project: Antioxidant Polyphenols in Impaired Brain and Heart Functions Associated with Obesity and Metabolic Diseases

Location: Diet, Genomics and Immunology Lab

Title: Influence of zinc deficiency on AKT-MDM2-P53 signaling axes in normal and malignant human prostate cells

Authors
item Han, Chung -
item Schoene, Norberta
item Lei, K -

Submitted to: American Journal of Physiology - Cell Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 3, 2009
Publication Date: August 5, 2009
Citation: Han, C.T., Schoene, N.W., Lei, K.Y. 2009. The influence of zinc deficiency on AKT-MDm2-p53 signaling axes in normal and malignant human prostate cells. American Journal of Physiology - Cell Physiology. 297(5):C1188-1199.

Interpretive Summary: Cells from the normal prostate and the malignant prostate differ in their handling of zinc, an essential mineral. To add to the understanding of how zinc can influence the growth of both normal and malignant cells, we studied the effects of different amounts of zinc on cellular signals that control growth. We found that when both prostatic cell types, the normal and the malignant, were exposed to lower than normal amounts of zinc, a signaling protein that leads to stopping cell growth by moving within the cell was restricted in the malignant cell line but not in the normal cell line. Our results demonstrated the importance of zinc metabolism in maintaining balanced growth in the prostate by modulating cellular communications. This finding adds to the informational database for known actions of this essential mineral and will be of interest to nutritionists and to researchers performing basic studies in nutritional aspects of cancer prevention.

Technical Abstract: With prostate being the highest zinc-accumulating tissue before the onset of cancer, the effects of physiologic levels of zinc on Akt-Mdm2-p53 and Akt-p21 signaling axes in human normal prostate epithelial cells (PrEC) and malignant prostate LNCaP cells were examined. Cells were cultured for 6 d in low-zinc growth medium supplemented with either 0 (zinc-deficient; ZD), 4 (zinc-normal; ZN), 16 (zinc-adequate; ZA), or 32 (zinc-supplemented; ZS) micromolar zinc. Zinc status of both cell types was altered in a dose-dependent manner. Also for both types, p-Akt was higher in ZD than ZN group and was normalized to that of ZN group by treatment with a PI3K inhibitor, LY294002. PTEN, an endogenous phosphatase targeting Akt de-phosphorylation, was found to be hyper-phosphorylated (inactive form) in zinc-deficient PrEC. Nuclear p-Mdm2 increased, while nuclear p53 was depressed by zinc deficiency in PrEC. Both nuclear p21 and p53 were lowered by zinc deficiency in LNCaP cells. Higher percentages of ZD-, ZA-, and ZS-LNCaP cells were found for the G0/G1 phase of cell cycle than ZN cells, with proportionally less at S and G2/M phases. Hence, the increased p-PTEN observed in zinc-deficient PrEC would result in hyper-phosphorylation of both p-Akt and p-Mdm2 as well as reduction in nuclear p53 accumulation. For zinc-deficient LNCaP cells, Akt hyper-phosphorylation was likely mediated through p21 phosphorylation and degradation, thus restricting p21 nuclear entry to induce cell cycle arrest. Thus, zinc deficiency differentially modulated the Akt-Mdm2-p53 signaling axis in normal prostate cells versus the Akt-p21 one in malignant prostate cells.

Last Modified: 9/22/2014
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