Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration

• DOI: 10.1007/s10534-016-9971-z
• Publication Date: 2016-09-21T14:28:02Z
• Authors: Nico Münnich; Simon Wernhart; Christer Hogstrand; Uwe Schlomann; Christopher Nimsky; Jörg W. Bartsch
• Keywords: Oxadiazoles; 0303 health sciences; Glycogen Synthase Kinase 3 beta; Brain Neoplasms; Ethylenediamines; Transfection; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Humans; Enzyme Inhibitors; Phosphorylation; Tumor Suppressor Protein p53; Glioblastoma; Cation Transport Proteins; Benzofurans; Chelating Agents

Zinc importer proteins (ZIPs) have been proven as important molecular regulators in different cancers. As a member of the solute carrier family, ZIP9/SLC39A9 is overexpressed in prostate and breast cancer and affects B-cell receptor signaling. Here, we present data indicating that changes in intracellular zinc levels in glioblastoma cells can cause enhanced cell survival and cell migration, both hallmarks of the disease process. In particular, treatment of human glioblastoma cells with sublethal doses of cell-permeable heavy metal (Zn2+ > Fe2+ > Mn2+) chelator (N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN)) induced ZIP9 expression. Either TPEN treatment or expression of ZIP9 cDNA causes enhanced migration behavior of glioblastoma cells. Compared to untreated glioblastoma cells TPEN treatment or expression of ZIP9 results in activation of the tumor suppressor p53 by phosphorylation at serine residue 46 (Ser46) and in inactivation of the migration relevant glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation at serine residue 9 (Ser9). Whilst p53 activation affects cell survival in response to TPEN, GSK-3β inactivation directly affects glioblastoma cell migration. Therefore, ZIP9 expression could regulate the migratory behavior of glioblastoma cells, so that ZIP9 may be of biological, but not of clinical relevance for glioblastomas, since in GBM tumor tissues, ZIP9 expression is not significantly increased compared to normal brain.