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 Table of Contents  
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 26-30

Thioredoxin-interacting Protein as a Common Regulation Target for Multiple Drugs in Clinical Therapy/Application

1 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Emergency, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China; Department of Biochemistry and Molecular Biology, Division of Molecular Medical Biochemistry, Shiga University of Medical Sciences, Shiga, Japan
3 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission12-Jan-2015
Date of Acceptance05-Feb-2015
Date of Web Publication16-Feb-2015

Correspondence Address:
Prof. Yanyang Tu
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA

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Source of Support: None, Conflict of Interest: None

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Initially identified in HL60 cells treated with Vitamin D3, thioredoxin-interacting protein (TXNIP) is considered as a major redox regulator and a potential connector between cellular redox state and metabolism. TXNIP plays an important role in the control of glucose and lipid metabolism, and it has been defined as a tumor suppressor gene in various solid tumors and hematological malignancies. This review gives an overview of the mechanism of various medicines including Lycium barbarum polysaccharide, Quercetin, trans-resveratrol, metformin, purple sweet potato color, nobiletin, taurine, suberoylanilide hydroxamic acid, and Theophylline, and their potential applications in the clinical treatment of many diseases.

Keywords: Clinical treatment, medicines, NLRP3 inflammasome, redox regulation, thioredoxin-interacting protein

How to cite this article:
Zhang P, Pang X, Tu Y. Thioredoxin-interacting Protein as a Common Regulation Target for Multiple Drugs in Clinical Therapy/Application. Cancer Transl Med 2015;1:26-30

How to cite this URL:
Zhang P, Pang X, Tu Y. Thioredoxin-interacting Protein as a Common Regulation Target for Multiple Drugs in Clinical Therapy/Application. Cancer Transl Med [serial online] 2015 [cited 2020 Aug 5];1:26-30. Available from: http://www.cancertm.com/text.asp?2015/1/1/26/151488

  Introduction Top

Mostly malignant tumor represents a form of incurable medical disorder with poor prognosis. It compromises the life quality of the patients worldwide. Along with the development of clinical medicine, the regulatory mechanisms of tumor formation process and the pathogenesis of various solid tumors or hematologic malignancies have been most heavily studied. [1] Therefore, researchers are clearly aware that tumor metabolic pathways are becoming important molecular targets for cancer therapy. The molecular mechanisms of many traditional drug treatments were found to participate in different metabolic pathways. Thioredoxin-interacting protein (TXNIP) and its related pathways were proved to be important molecular therapeutic targets. [2],[3],[4] for the reasons above, TXNIP was widely and deeply studied.

TXNIP, a multifunctional protein, which is also titled as Vitamin D3 up-regulating protein 1 or thioredoxin binding protein-2, is implicated in cell proliferation differentiation and apoptosis. Besides the central role in cancers and other stress-related diseases, [2],[3],[4] TXNIP is also an important regulator of glucose and lipid metabolism. [5],[6] TXNIP contains two typical arrestin-like domains with PXXP or PPXY sequence, which are known as binding motif for SH3-domains containing proteins, for example trithorax (Trx), and WW-domain, for example NLRP3 respectively. [7],[8],[9]

Excessive reactive oxygen species (ROS) are involved in various pathological conditions. [10] As a main redox regulator, TXNIP negatively regulates Trx expression and its antioxidant function through combining with Trx, and such regulation is critical in the control of DNA damage and apoptosis. [11] In addition, ROS is the major activator of the NLRP3 inflammasome. [12] Inflammasomes are a group of large caspase-1-activating protein complexes in response to the resulting of innate immunity and production of pro-inflammatory cytokines. [13] Inflammasomes, particularly NLRP3 inflammasome, are shown to be activated in a series of liver diseases, including drug-induced liver injury, [14] viral hepatitis, [15] endotoxin-induced liver injury and cholestasis, [16],[17] fibrosis, [18] ischemia-reperfusion (I/R) injury, [19] and nonalcoholic fatty liver disease. [20],[21] And many studies showed that the physical interaction between TXNIP and NLRP3 may explain the inflammasome activation in a ROS-sensitive manner. [12]

Here, we summarize the major role of TXNIP acting as a common regulation target for multiple medicines including Lycium barbarum polysaccharide (LBP), Quercetin, trans-resveratrol (T-res), Metformin, purple sweet potato color (PSPC), Nobiletin, Taurine, Suberoylanilide hydroxamic acid (SAHA), and Theophylline mediated in the clinical treatment [Table 1]. We also highlight the potential strategies used to reactivate TXNIP expression for cancer therapeutics.
Table 1: The mechanism of various medicines regulated TXNIP related pathway

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  Lycium Barbarum Polysaccharide Regulates the Thioredoxin-Interacting Protein-NLRP3 Inflammasome Pathway Top

Lycium barbarum polysaccharide (LBP) is a traditional Chinese medicine used in liver, kidney and eye diseases. [22],[23] In drug-induced acute liver injury model and high-fat diet-induced NAFLD model, LBP is shown to lessen hepatic dysfunction, such as inflammation, oxidative stress, apoptosis, lipid deposition, and histological changes. [23],[24]

Xiao et al.,[25] have found that 50 μg/mL LBP pretreatment significantly attenuated over-expression of TXNIP under 24-h ethanol exposure-induced, and was accompanied with the increasing of cellular apoptosis, activation of NLRP3 inflammasome, secretion of inflammatory cytokines, production of ROS, and antioxidant enzyme down expression. In addition, silence of TXNIP could inhibit NLRP3 inflammasome activation, promote oxidative stress and worsen apoptosis in cells. These results indicated that LBP contributes to the attenuation of cellular apoptosis, oxidative stress and inflammation lesions via inhibition of hepatic TXNIP-NLRP3 inflammasome pathway.

  Quercetin Inhibits AMP Activated Kinase/Thioredoxin-Interacting Protein Activation and Reduces Inflammatory Lesions Top

Quercetin, a traditional therapeutic for high fructose-induced insulin resistance and hyperlipidemia, has multiple bioactivities including anti-oxidation, anti-inflammation, anti-hyperlipidemia and anti-diabetes. [26],[27] Zhang et al.[28] investigated the regulatory effects of Quercetin on the hypothalamus in high fructose-fed rats. Then they found that Quercetin inhibits AMP activated kinase (AMPK)/TXNIP and its downstream pathway of Nuclear factor-κB (NF-κB)/NLRP3 inflammasome activation in vivo. The result meant that it may be associated with the reduction of hypothalamic inflammatory lesions, benefiting to the improvement of hypothalamic insulin signaling defect in this model.

  Trans-Resveratrol Downregulates Thioredoxin-Interacting Protein Overexpression During Liver Ischemia-Reperfusion Top

Trans-resveratrol is a well-known natural phytoalexin with anti-oxidative, anti-apoptotic and anti-proliferative effects. [29] In isolated perfused liver and cultured hepatocytes, T-res has been reported to possess the protective properties against oxidative stress. [30],[31] Nivet-Antoine et al.[32] studied the effects of a postischemic treatment of T-res on the liver Trx/TXNIP system. Finally, they found the liver I/R upregulated hepatic TXNIP expression. Meanwhile, T-res would suppress the over-expression of I/R TXNIP. It is obvious that the decrease of TXNIP expression by T-res was associated with an increase in liver Trx redox activity.

  Metformin Suppresses Thioredoxin-Interacting Protein Gene Expression to Maintain Glucose Homeostasis Top

Metformin is suggested as a conventional therapeutic for type-II diabetes mellitus to control the blood sugar level. [33] It is reported that TXNIP plays major role in glucose metabolism through inhibiting cellular glucose uptake and metabolism, as well as enhancing hepatic gluconeogenesis. [34],[35],[36]

Chai et. al.[37] demonstrated metformin significantly reduced TXNIP mRNA and protein expression in cultured cells. The main reason is that the inhibition of mitochondrial complex I and increased glycolysis are partially associated with the AMPK. Moreover, the recruiting of Mondo: MLX to the TXNIP gene promoter also decreased, indicating that the transcription of the TXNIP gene is inhibited by metformin. These observations propose that the novel action of metformin on the TXNIP gene expression may contribute to the therapeutic effects on type II diabetes treatment.

  Purple Sweet Potato Color Inhibits Oxidative Stress-Mediated Thioredoxin-Interacting Protein/NLRP3 Inflammasome Activation Top

Inflammation has important effect on the pathogenesis of obesity. [38] PSPC was reported to have a potential anti-inflammation efficacy. [39] Shan et al.[40] showed PSPC could significantly lessen the kidney NLRP3 inflammasome activation, inhibit I kappa B kinase b activation, block the nuclear translocation of NF-kB, and reduce the oxidative stress-associated AGE receptor (RAGE) and TXNIP expression level. These data implied that the advantageous roles of PSPC on high fat diet-induced kidney disorder and damage are associated with TXNIP/NLRP3 signaling pathways, providing a potential target for obesity.

  Nobiletin Downregulates Thioredoxin-Interacting Protein Expression Top

Nobiletin, a citrus polymethoxy flavonoid with six methoxy groups, was presented abundantly in the peels of citrus fruits. [41] Over-expression of TXNIP has recently been considered as a crucial factor for irremediable endoplasmic reticulum (ER) stress leading to the programmed cell death of pancreatic β-cell. [42],[43] Ikeda et al.[44] confirmed that nobiletin decreased both the tunicamycin-induced cellular apoptosis and the subsequent suppression of TXNIP over-expression. Therefore, it is possible that nobiletin can improve ER stress-induced neurological disorders partly via suppressing TXNIP expression. The future study for this mechanism would provide novel insights not only into nobiletin's beneficial actions on various human diseases, but also into the functions of TXNIP in those diseases.

  Effect of Taurine on MRNA Expression of Thioredoxin-Interacting Protein Top

Taurine (also titled as 2-aminoethanesulfonic acid), a sulfur-containing β-amino acid, plays significant role in numerous essential biological processes. [45] In order to explore the potential mechanisms for these regulatory functions, especially at the genetic level, Gondo et al.[46] investigated the effects of taurine on the gene expression profile (GEP) by means of DNA microarray in Caco-2 cells. The results showed that Taurine increased the TXNIP mRNA expression and promoter activity. However, β-alanine or c-aminobutyric acid, which structurally or functionally related to taurine, did not increase TXNIP mRNA and protein expression. The study verified the taurine-specific physiological function of TXNIP up-regulation.

  Histone Deacetylation Inhibitors Suberoylanilide Hydroxamic Acid-Mediated Repression of Thioredoxin-Interacting Protein Expression Top

Suberoylanilide hydroxamic acid was received Food and Drug Administration approval in 2006 for the treatment of refractory cutaneous T-cell lymphoma. [47] Moreover, it is currently in clinical trials for acute myeloid leukemia and myelodysplastic syndromes. However, its mechanism of action is unclear. Butler et al.[48] performed GEP of prostate cancer cell line LNCaP with SAHA treatment in a time-dependent manner. The studies proved that treatment with SAHA increased the expression of TXNIP, resulting in attenuating Trx expression and activity in cancer cells but not normal cells, switched Trx1 oxidation state toward a more oxidized one, and complex formation with Trx1. Complex formation with Trx1 further leads to the accumulation of ROS. This study indicated that one possible mechanism for the anticancer effect of SAHA is via the Trx1/TXNIP system. [48],[49],[50]

  Theophylline Regulates Inflammatory and Neurotrophic Factor Signals Top

Theophylline is widely used in the clinical treatment of asthma, chronic pulmonary obstructive disease, and premature infants with respiratory deficits. [51],[52],[53] Singh et al.[54] provided the first evidence that theophylline-induced respiratory recovery in the C2H model is associated with induction of both neurotrophic factors (brain derived neurotrophic factor, glial cell line-derived neurotrophic factor, and Bcl2) and pro-inflammatory genes (TXNIP, interleukin-1β (IL-1β), tumor necrosis factor-α and inducible nitric-oxide synthase). And the findings in this study demonstrated that the elevated levels of TXNIP/NF-κB/IL-1β pathway were in agreement with the results reported by Perrone et al.,[55] whose study demonstrated that TXNIP/NF-κB/IL-1β axis was involved in recovery of partial sciatic nerve injury and primary Schwann cell activation. Therefore, the enhanced resolution of early inflammatory processes and expression of pro-survival factors may be the potential treatment targets and intracellular signals underling theophylline-induced respiratory recovery.

  Conclusions and Therapeutic Implications Top

In summary, TXNIP mediates oxidative stress via binding and inhibition of Trx, a major ROS scavenger with multifunction. Lack of TXNIP promotes cell proliferation and protects cell against apoptosis. Abundant researches and clinical studies have confirmed that TXNIP acts as a tumor suppressor in various malignancies. It appears that the cancer cells have developed multiple ways to inactivate TXNIP, indicating the importance of repression of TXNIP in tumorigenesis. As such, regulation of TXNIP expression could be a new and viable approach for epigenetic therapies through the use of either LBP, quercetin, T-res, metformin, PSPC, nobiletin, taurine, SAHA, theophylline or in combination fashion [Figure 1].
Figure 1: TXNIP is signaling pathways and medicines functions. ⊥signs indicate inhibition and ↓signs indicate activation. LBP: Lycium barbarum polysaccharide; SAHA: Suberoylanilide hydroxamic acid; T-res: Trans-resveratrol; PSPC: Purple sweet potato color; TXNIP: Thioredoxin-interacting protein; Trx: Trithorax; ROS: Reactive oxygen species; ER: Endoplasmic reticulum

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Further characterizing TXNIP functions, including its role in Trx regulation, NLRP3 inflammasome activation, and glucose metabolism, would not only provide new insights into epigenetic repression of TXNIP in cancer biology, but also offer new therapeutic approaches to the treatment and prevention of cancer.

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