Hyperglycemia regulates thioredoxin-ROS activity through induction of thioredoxin-interacting protein (TXNIP) in metastatic breast cancer-derived cells MDA-MB-231

Abstract

Background: We studied the RNA expression of the genes in response to glucose from 5 mM (condition of normoglycemia) to 20 mM (condition of hyperglycemia/diabetes) by microarray analysis in breast cancer derived cell line MDA-MB-231. We identified the thioredoxin-interacting protein (TXNIP), whose RNA level increased as a gene product particularly sensitive to the variation of the level of glucose in culture media. We investigated the kinesis of the TXNIP RNA and protein in response to glucose and the relationship between this protein and the related thioredoxin (TRX) in regulating the level of reactive oxygen species (ROS) in MDA-MB-231 cells.

Cancer Risk Among People With Type 1 and Type 2 Diabetes: Disentangling True Associations, Detection Bias, and Reverse Causation

“…Our results, instead, support the concept that hyperglycemia, found in both type 1 and type 2 diabetes, may be the mechanistic driver between diabetes and cancer. Hyperglycemia can induce DNA damage (26), downregulate expression of antioxidants (27), and increase reactive oxygen species generation (28). Although biologically plausible, results from epidemiological studies are conflicting.…”

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

“…Of major importance is the observation that TXNIP production is robustly induced by glucose in islets as well as other tissues [8][9][10][11]. Glucose regulates TXNIP mainly at the level of transcription, and promoter analysis of the human TXNIP gene identified a distinct carbohydrate response element consisting of a non-palindromic repeat of two E-boxes conferring glucose responsiveness [12].…”

An Evolutionary and Mechanistic Perspective on Dietary Carbohydrate Restriction in Cancer Prevention

“…While there are numerous intracellular control mechanisms, the insulin-glucose axis exerts a predominant effect and provides a stimulus for excessive growth and mutagenesis [15] as well as support for excessive biomass production required during the progression of cancer [16]. The hyperinsulinemic/hyperglycemic state also may appear as increased mitochondrial reactive oxygen species which, in turn, are likely to have a mutagenic effect [17][18][19]. Reduced insulin signaling, therefore, is expected to have beneficial effects in tumor suppression and is not excluded as the effect of total caloric restriction.…”

“…High blood glucose concentrations -especially those experienced during spikes in poorly-controlled type 2 diabetics -stimulate production of free radicals and especially reactive oxygen species (ROS) [18,19,82]: Figure 3). Hyperglycemia induces increased ROS in breast cancer cell lines [17,83] presumably contributing to genomic instability. Cancer cells appear to protect themselves from intrinsically high steady state levels of ROS by increasing the rate of glycolysis and activation of the pentose phosphate pathway, both resulting in production of high levels of the anti-oxidative pyruvate and lactate as well as NADPH, stabilizing reduced glutathione [84,85].…”