Intracellular zinc increase inhibits p53 −/− pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis

• Published in: Biochimica et biophysica acta 2009-02, Vol.1793 (2), p.273-280
• Main Authors: Donadelli, M., Dalla Pozza, E., Scupoli, M.T., Costanzo, C., Scarpa, A., Palmieri, M.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Apoptosis - drug effects; Apoptosis Inducing Factor - metabolism; Caspases - metabolism; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Ethylenediamines - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Leupeptins - pharmacology; Mitochondria - drug effects; Mitochondria - enzymology; Models, Biological; Oxidative stress; p53; Pancreatic adenocarcinoma; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Transport - drug effects; Pyrrolidine dithiocarbamate; Pyrrolidines - pharmacology; Reactive Oxygen Species - metabolism; Thiocarbamates - pharmacology; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Zinc; Zinc - metabolism
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2008.09.010

We show that treatment with non-toxic doses of zinc in association to the ionophore compound pyrrolidine dithiocarbamate (PDTC) inhibits p53 −/− pancreatic cancer cell growth much more efficiently than gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Both the metal chelator N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine and the radical scavenger N-acetyl- l-cysteine are able to recover cell growth inhibition by Zn/PDTC, demonstrating that this effect depends on the increased levels of intracellular zinc and of reactive oxygen species (ROS). Zn/PDTC treatment induces a strong apoptotic cell death that is associated to ROS-dependent nuclear translocation of the mitochondrial factor AIF, but not to the regulation of apoptotic genes and caspase activation. Primary fibroblasts are more resistant than pancreatic cancer cells to Zn/PDTC treatment and exhibit a lower basal and Zn/PDTC-induced enhancement of intracellular zinc. We show that Zn/PDTC induces p53 proteasomal degradation and that the proteasome inhibitor MG132 further increases fibroblast growth inhibition by Zn/PDTC, suggesting that p53 degradation plays an important role in fibroblast resistance to Zn/PDTC.