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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/C1188    most recent 00042.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Han, C.-T. Articles by Lei, K. Y. PubMed PubMed Citation Articles by Han, C.-T. Articles by Lei, K. Y.

Cellular and Mitochondrial Metabolism

Influence of zinc deficiency on Akt-Mdm2-p53 and Akt-p21 signaling axes in normal and malignant human prostate cells

¹Department of Nutrition and Food Science, University of Maryland, College Park; ²Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, Maryland; and ³Nutritional Sciences Biotechnology Laboratory and Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Kingdom of Saudi Arabia

Submitted 22 January 2009 ; accepted in final form 3 August 2009

Phosphorylated Akt (p-Akt), a phosphoinositide-3-OH-kinase-activated protein kinase, is highly expressed in prostate tumors. p-Akt can indirectly hinder p53-dependent growth suppression and apoptosis by phosphorylating Mdm2. Alternatively, p-Akt can directly phosphorylate p21 and restrict it to the cytoplasm for degradation. Because the prostate is the highest zinc-accumulating tissue before the onset of cancer, the effects of physiological 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 in the present study. Cells were cultured for 6 days in low-zinc growth medium supplemented with 0 [zinc-deficient (ZD)], 4 [zinc-normal (ZN)], 16 [zinc-adequate (ZA)], or 32 [zinc-supplemented (ZS)] µM zinc. Zinc status of both cell types was altered in a dose-dependent manner, with LNCaP cells reaching a plateau at >16 µM zinc. For both cell types, p-Akt was higher in the ZD than in the ZN cells and was normalized to that of the ZN cells by treatment with a PI3K inhibitor, LY-294002. PTEN, an endogenous phosphatase targeting Akt dephosphorylation, was hyperphosphorylated (p-PTEN, inactive form) in ZD PrEC. Nuclear p-Mdm2 was raised, whereas nuclear p53 was depressed, by zinc deficiency in PrEC. Nuclear p21 and p53 were lowered by zinc deficiency in LNCaP cells. Higher percentages of ZD, ZA, and ZS than ZN LNCaP cells were found at the G₀/G₁ phase of the cell cycle, with proportionally lower precentages at the S and G₂/M phases. Hence, the increased p-PTEN in ZD PrEC would result in hyperphosphorylation of p-Akt and p-Mdm2, as well as reduction of nuclear p53 accumulation. For ZD LNCaP cells, Akt hyperphosphorylation was probably 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 vs. the Akt-p21 signaling axis in malignant prostate cells.

zinc status; cell cycle progression; signal transduction