Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Carcinoma, Pancreatic Ductal / drug therapy
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / pathology
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Carcinoma, Pancreatic Ductal / physiopathology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Diabetes Mellitus / etiology
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Female
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Gene Silencing
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Humans
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Hyperglycemia / etiology*
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Immunohistochemistry
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MAP Kinase Signaling System* / drug effects
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Male
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Oxidative Stress / drug effects
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Pancreas / drug effects
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Pancreas / metabolism
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Pancreas / pathology
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Pancreas / physiopathology
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / physiopathology*
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RNA, Small Interfering
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Reactive Oxygen Species / metabolism*
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Thioredoxins / metabolism*
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Up-Regulation / drug effects
Substances
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Antineoplastic Agents
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Carrier Proteins
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Neoplasm Proteins
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RNA, Small Interfering
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Reactive Oxygen Species
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TXN protein, human
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TXNIP protein, human
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Thioredoxins