title: 2-Deoxyglucose induces the expression of thioredoxin interacting protein (TXNIP) by increasing O-GlcNAcylation - Implications for targeting the Warburg effect in cancer cells.
abstract: The high proliferation rate of cancer cells and the microenvironment in the tumor tissue require the reprogramming of tumor cell metabolism. The major mechanism of metabolic reprogramming in cancer cells is the Warburg effect, defined as the preferential utilization of glucose via glycolysis even in the presence of oxygen. Targeting the Warburg effect is considered as a promising therapeutic strategy in cancer therapy. In this regard, the glycolytic inhibitor 2-deoxyglucose (2DG) has been evaluated clinically. 2DG exerts its effect by directly inhibiting glycolysis at the level of hexokinase and phosphoglucoisomerase. In addition, 2DG is also known to induce the expression of thioredoxin interacting protein (TXNIP), a tumor suppressor protein and an important negative regulator of cellular glucose uptake. Hence, characterization of the mechanism through which 2DG regulates TXNIP expression may reveal novel approaches to target the Warburg effect in cancer cells. Therefore, in this study we sought to test various hypotheses for the mechanistic basis of the 2DG dependent TXNIP regulation. We have shown that 2DG induced TXNIP expression is independent of carbohydrate response element mediated transcription. Furthermore, the induction of TXNIP is neither dependent on the ability of 2DG to deplete cellular ATP nor to cause endoplasmic reticulum stress. We found that the 2DG induced TXNIP expression is at least in part dependent on the inhibition of the O-GlcNAcase enzyme and the accumulation of O-GlcNAc modified proteins. These results have implications for the identification of therapeutic targets to increase TXNIP expression in cancer.
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
authors: Shin Yee
authors: SY
authors: Hong
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore. Electronic address: bchth@nus.edu.sg.
authors: Thilo
authors: T
authors: Hagen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004285:Dogs; D059865:Endoplasmic Reticulum Stress; D006019:Glycolysis / Q000187:drug effects*; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D009363:Neoplasm Proteins; D013879:Thioredoxins; D000255:Adenosine Triphosphate; D003847:Deoxyglucose
keywords: 2-Deoxyglucose; ChoRE; MondoA; O-GlcNAcylation; TXNIP