The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma
Open Access
- 9 July 2014
- journal article
- Published by Informa UK Limited in Cancer Biology & Therapy
- Vol. 15 (10), 1431-1437
- https://doi.org/10.4161/cbt.29927
Abstract
Pancreatic cancer (ductal adenocarcinoma) remains a deadly cancer with ~85% mortality, and a 5-year survival rate of ~6% or less for the past 30 years. The factors and events associated with the development of pancreatic cancer are poorly identified. As such, effective biomarkers for early detection of malignancy are lacking. Efficacious chemotherapy once the cancer is identified does not exist. Recent clinical studies have revealed that the zinc levels are consistently and markedly decreased in adenocarcinoma as compared with normal/benign pancreatic tissue. The decreased zinc is exhibited in well-differentiated malignancy and in progressing malignancy, and also exists throughout the development of PanIN. Concurrent with the decrease in zinc, RREB1 transcription factor and ZIP3 zinc uptake transporter are downregulated. Thus, a RREB1/ZIP3/Zinc transformation appears to be an early event in the development of pancreatic cancer. We propose that this transformation is necessary to prevent the accumulation of high cellular zinc levels, which result in cytotoxic effects on the developing malignant cells. This report now demonstrates that exposure of Panc1 cells to physiological concentrations of zinc that result in increased zinc uptake and accumulation also inhibits cell proliferation. The study further shows that ZIP3 is the important transporter required for the accumulation of zinc and its inhibition of proliferation. RREB1 is identified as the positive regulator of ZIP3 expression. Therefore, the pathway of RREB1/ZIP3/Zinc and its downregulation during oncogenesis exist to prevent the accumulation of cytotoxic levels of zinc during the development and progression of the malignant cells in pancreatic adenocarcinoma.Keywords
This publication has 39 references indexed in Scilit:
- A novel epigenetic CREB‐miR‐373 axis mediates ZIP4‐induced pancreatic cancer growthEMBO Molecular Medicine, 2013
- Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cellsJournal of Inorganic Biochemistry, 2011
- Characterization of the promoter region of TCblR/CD320 gene, the receptor for cellular uptake of transcobalamin-bound cobalaminGene, 2010
- Down-regulation of ZIP4 by RNA Interference Inhibits Pancreatic Cancer Growth and Increases the Survival of Nude Mice with Pancreatic Cancer XenograftsClinical Cancer Research, 2009
- KRAS2 Mutations in Human Pancreatic Acinar-Ductal Metaplastic Lesions Are Limited to Those with PanIN: Implications for the Human Pancreatic Cancer Cell of OriginMolecular Cancer Research, 2009
- The important role of the apoptotic effects of zinc in the development of cancersJournal of Cellular Biochemistry, 2009
- Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasiaProceedings of the National Academy of Sciences of the United States of America, 2008
- Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progressionProceedings of the National Academy of Sciences of the United States of America, 2007
- Zinc as an anti-tumor agent in prostate cancer and in other cancersArchives of Biochemistry and Biophysics, 2007
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976