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.