Hyperglycemia Regulates TXNIP/TRX/ROS Axis via p38 MAPK and ERK Pathways in Pancreatic Cancer
Katie M. Reindl,
Approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes because high
glucose levels can contribute to oxidative stress which promotes tumor development. As one of the reactive oxygen
species (ROS)-regulating factors, thioredoxin-interacting protein (TXNIP), is involved in the maintenance of thioredoxin
(TRX)-mediated redox regulation. In this study, we demonstrated that high glucose levels increased the expression of
TXNIP in time- and concentration-dependent manners and modulated the activity of TRX and ROS production in
pancreatic cancer cells, BxPC-3 and Panc-1. We also found that glucose activated both p38 MAPK and ERK pathways
and inhibitors of these pathways impaired the TXNIP/TRX/ROS axis. Knockdown of TXNIP restored TRX activity and
decreased ROS production under high glucose conditions. Moreover, we observed that the integrated optical density
(IOD) of TXNIP staining as well as the protein and mRNA expression levels of TXNIP were higher in the tumor tissues
of pancreatic cancer patients with diabetes. Taken together, these results indicate that hyperglycemia-induced TXNIP
expression is involved in diabetes-mediated oxidative stress in pancreatic cancer via p38 MAPK and ERK pathways.
Keywords: Glucose, MAPK pathway, pancreatic cancer, ROS, TXNIP.
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