The influence of zinc deficiency on Akt signaling pathway in human prostate

Abstract

The phosphorylated form of Akt, a phosphoinositide-3-OH-kinase (PI3K) activated protein kinase, is highly expressed in prostate tumors. Supra-physiological level of zinc has been shown to stimulate the phosphorylation of Akt in cell culture. Conversely, zinc has been established to be depleted in prostate cancer cells. The objective of this study was to determine whether zinc depletion influences the cell cycle regulation and apoptosis via Akt signaling pathway. Human primary normal prostate epithelial cells and human prostate cancer cell line (LNCaP) were cultured in zinc-free normal growth medium (< 0.1 μM zinc) supplemented with 0, 0.4, 4, 16, or 32 μM of zinc. Both zinc-deficient treatments, namely 0 and 0.4 μM, lowered cellular zinc levels by 40 and 30% in normal prostate and LNCaP cells, respectively, than zinc-adequate counterparts. The levels of phosphorylated Akt were twofold higher in zinc-deficient LNCaP cells than in zinc-adequate cells. By using a specific inhibitor of PI3K/Akt pathway, LY294002, the elevated Akt phosphorylation observed in zinc-deficient LNCaP cells was normalized to that of zinc-adequate cells. In summary, cellular zinc status was susceptible to the availability of zinc in culture media. The use of PI3K/Akt inhibitor demonstrated that zinc deficiency-induced Akt phosphorylation in LNCaP cells was dependent on this signaling pathway. In particular, Akt can phosphorylate Mdm2 and enhance its nuclear entry, subsequently promoting the ubiquitin-dependent degradation of tumor suppressor p53. As a result, Akt can indirectly hinder p53-dependent growth suppression and apoptosis. (Supported by USDA NRI 2002-35200-12241)