AMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1

Wu, Ning; Zheng, Bin; Shaywitz, Adam J.; Dagon, Yossi; Tower, Christine; Bellinger, Gary; Shen, Che Hung; Wen, Jennifer; Asara, John M.; McGraw, Timothy E.; Kahn, Barbara B.; Cantley, Lewis C.

doi:10.1016/j.molcel.2013.01.035

Cited by 564 publications

(592 citation statements)

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“…Glucose availability affects ROS production in cells, and high glucose uptake induces cellular senescence (Mortuza et al, 2013). Previous reports have revealed that TXNIP regulates glucose uptake in peripheral tissues in both an insulin‐dependent and insulin‐independent manner and suppresses glucose uptake by regulating the expression and internalization of GLUT1 (Parikh et al, 2007; Wu et al, 2013). From these previous reports, we hypothesized that TXNIP might regulate cellular senescence by regulating the balance of glucose uptake and ROS production.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we examined the induction of glucose uptake in KO MEF cells (Figure 1i) and KO mice (Figure 4a,b, 5a, and Supporting Information Figure S4D). Although previous reports have revealed the role of TXNIP in the regulatory mechanisms of glucose uptake and glucose metabolism in cancer and primary cells, the function of TXNIP in cellular senescence under glucose stress has not been reported (DeBalsi et al, 2014; Hui et al, 2008; Wu et al, 2013). High glucose is a well‐known inducer of cellular ROS and accelerates the senescence of cells (Mortuza et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…TXNIP is a well‐known tumor suppressor and pro‐oxidant protein that inhibits TRX activity via direct interaction with the catalytic active center of TRX (Jung & Choi, 2014). Apart from the tumor‐suppressing function of TXNIP in cancer cells, many reports have suggested that TXNIP regulates glucose homeostasis by inhibiting glucose uptake and glucose metabolism (Chutkow et al, 2008; Parikh et al, 2007; Wu et al, 2013). Here, we examined the induction of glucose uptake in KO MEF cells (Figure 1i) and KO mice (Figure 4a,b, 5a, and Supporting Information Figure S4D).…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have examined the role of TXNIP in glucose uptake and metabolism. TXNIP was shown to suppress glucose uptake by regulating glucose transporter 1 (GLUT1) localization and expression (Wu et al, 2013) and peripheral glucose metabolism (Parikh et al, 2007), and its expression in the liver is required for maintaining normal fasting glycemia and glucose production (Chutkow, Patwari, Yoshioka, & Lee, 2008). TXNIP regulates glycolysis and cell growth by reductive reactivation of phosphatase and tensin homolog (PTEN), and TXNIP deficiency results in protein kinase B (AKT) activation in oxidative tissues (Hui et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP‐/‐ MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and N‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP‐/‐ MEF cells. Interestingly, TXNIP‐/‐ MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP‐/‐ MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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“…The binding site of HIF-1-alpha, namely the hypoxia response element (HRE), is present in the human and rat GLUT1 promoter regions (Behrooz and Ismail-Beigi 1997;Zelzer et al 1998). Recently, Wu et al (2013) reported that knockdown of thioredoxin interacting protein (TXNIP) expression increased GLUT1 expression in HepG2 hepatocellular carcinoma cells, but the details of the regulatory mechanism are unknown. TXNIP was originally cloned as a 1α,25-dihydroxy vitamin D 3 -inducible protein in HL-60 cells (Chen and DeLuca 1994).…”

Section: Introductionmentioning

confidence: 99%

D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression

Noguchi

Kamitori

Hossain

et al. 2016

Tohoku J. Exp. Med.

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Glucose is a major energy source for mammalian cells and is transported into cells via cell-specific expression of various glucose transporters (GLUTs). Especially, cancer cells require massive amounts of glucose as an energy source for their dysregulated growth and thus over-express GLUTs. d-allose, a C-3 epimer of d-glucose, is one of rare sugars that exist in small quantities in nature. We have shown that d-allose induces the tumor suppressor gene coding for thioredoxin interacting protein (TXNIP) and inhibits cancer cell growth by G1 cell cycle arrest. It has also been reported that GLUTs including GLUT1 are overexpressed in many cancer cell lines, which may contribute to larger glucose utilization. Since d-allose suppresses the growth of cancer cells through the upregulation of TXNIP expression, our present study focused on whether d-allose down-regulates GLUT1 expression via TXNIP expression and thus suppresses cancer cell growth. Western blot and real-time PCR analyses revealed that d-allose significantly induced TXNIP expression and inhibited GLUT1 expression in a dose-dependent manner in three human cancer cell lines: hepatocellular carcinoma (HuH-7), Caucasian breast adenocarcinoma (MDA-MB-231), and neuroblastoma (SH-SY5Y). In these cell lines, d-allose treatment inhibited cell growth. Importantly, d-allose treatment decreased glucose uptake, as measured by the uptake of 2-deoxy d-glucose. Moreover, the reporter assays showed that d-allose decreased the expression of luciferase through the hypoxia response element present in the tested promoter region. These results suggest that d-allose may cause the inhibition of cancer growth by reducing both GLUT1 expression and glucose uptake.

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Attacking the supply wagons to starve cancer cells to death

et al. 2016

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The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

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AMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1

Cited by 564 publications

References 51 publications

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression

Attacking the supply wagons to starve cancer cells to death

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