Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide

Abstract

Diabetes mellitus and pancreatic cancer are intimately related. Hyperglycemia, a chronic abnormality in diabetes, has been proved to be an independent predictor of mortality from cancer of the pancreas. However, little is known regarding the effect of hyperglycemia on pancreatic cancer cells. The aim of the present study was to evaluate whether increases in glucose concentration modulate the invasive and migratory potential of cancer cells, contributing to their enhanced metastatic behavior. Human pancreatic cancer cells BxPC-3 and Panc-1 were cultured in 5.5, 25 or 55 mM glucose for 12, 24 or 48 h in the absence or presence of superoxide dismutase and catalase. The intracellular reactive oxygen species were determined using 2,7-dichlorodihydrofluorecein diacetate. Wound healing assay and transwell invasion assay were used to detect the migratory and invasive potential of cancer cells. The invasion-related factor, urokinase plasminogen activator, was measured by RT-PCR and Western blot analysis. The production of reactive oxygen species was increased by glucose in a concentration-dependent manner. High glucose significantly enhanced the cell migration and invasion potential. Meanwhile, the expression of urokinase plasminogen activator was also increased. Superoxide dismutase-dependent production of hydrogen peroxide led to increased cell invasive and migratory ability and the expression of urokinase plasminogen activator. These increases were reversed by the hydrogen peroxide-detoxifying enzyme catalase. These results suggest that the association between hyperglycemia and poor prognosis in pancreatic cancer can be attributed to the alterations of the migratory and invasive ability of the cells through the production of hydrogen peroxide.