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

Abstract

Abstract. Diabetes mellitus and pancreatic cancer are intimately related. Hyperglycemia, a chronic abnomality 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 concentrationdependent 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 peroxidedetoxifying 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.

High Glucose Promotes Tumor Invasion and Increases Metastasis-Associated Protein Expression in Human Lung Epithelial Cells by Upregulating Heme Oxygenase-1 via Reactive Oxygen Species or the TGF-β1/PI3K/Akt Signaling Pathway

“…In our study, we investigated cellular invasion and the role of HO-1 using a Transwell chamber, and the results demonstrated that HG enhanced the capacity of A549 cell invasiveness. Similar studies have been described in A549 cells, pancreatic cancer cells and a human breast cancer cell line [12,59,60]. This finding was also supported by the report that HG levels contribute to tumor formation and progression in A549 cells [7] However, this invasiveness potential was deterred by HO-1 knockdown, which suggested that the HG-enhanced invasiveness potential was mediated by HO-1.…”

“…Several lines of evidence have indicated that HG enhances the invasiveness potential of MCF-7 breast cancer cells [44,59] and of pancreatic cancer cells [45,60]. Furthermore, previous studies have indicated that HO-1 positively correlates with tumor stage and lymph node metastasis and that HO-1 is associated with NSCLC progression [31].…”

Hyperglycemia, a Neglected Factor during Cancer Progression

“…Unfortunately, little attention has been focused on the role of hyperglycemia in inducing the cancer cell EMT phenotype. Our results demonstrated that high glucose could increase the production of ROS in the PC cell lines BxPC-3 and Panc-1, which further leads to cell motility and invasiveness [86]. We hypothesized that hyperglycemia facilitates PC metastasis by EMT induction and vascular destruction via oxidative stress [87].…”

Effect of glycemic control on the risk of pancreatic cancer

“…Hyperglycemia is associated with increased reactive oxygen species production and oxidative stress, which may be involved in the pathogenesis and invasiveness of pancreatic cancer. [8–10,27] Insulin resistance-related hyperinsulinemia might increase cancer progression by increasing cell proliferation, decreasing apoptosis, and enhancing cell responsiveness to other growth factors such as insulin-like growth factor. [19,28,29] Diabetes might alter the regulation of hormones such as adiponectin and leptin, which in turn leads to cancer growth via multiple signaling pathways.…”