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Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2009 Feb; Vol. 1793 (2), pp. 273-80. Date of Electronic Publication: 2008 Oct 07. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Adenocarcinoma 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
Pancreatic Neoplasms metabolism
Protein Transport drug effects
Pyrrolidines pharmacology
Thiocarbamates pharmacology
Tumor Suppressor Protein p53 genetics
Adenocarcinoma pathology
Apoptosis drug effects
Apoptosis Inducing Factor metabolism
Pancreatic Neoplasms pathology
Reactive Oxygen Species metabolism
Tumor Suppressor Protein p53 deficiency
Zinc metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1793
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 18951928
- Full Text :
- https://doi.org/10.1016/j.bbamcr.2008.09.010