Thioredoxin-Interacting Protein in Cancer and Diabetes

Masutani, Hiroshi

doi:10.1089/ars.2021.0038

Cited by 32 publications

(24 citation statements)

References 196 publications

(332 reference statements)

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“…AP is an unpredictable and potentially lethal disease [32]. In this study, we demonstrated, for the first time, that GSDMD was overexpressed in the ER of acinar cells, which exacerbated AP by the TXNIP/HIF-1α pathway.…”

Section: Discussionmentioning

confidence: 59%

“…Meanwhile, DSF significantly downregulated the level of GSDMD in the ER (Figure 2hi-iii). TXNIP is related to ROS bursts in cells, which meditates ERS [14,32]. A study revealed that the accumulation of GSDMD in the mitochondria increases cytochrome C release by increasing mitochondrial permeability [14], which may lead to an increase in ROS.…”

Section: Inhibition Of Gsdmd Accumulation In Endoplasmic Reticulum Am...mentioning

confidence: 99%

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Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

et al. 2022

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Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.

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Section: Discussionmentioning

confidence: 59%

Section: Inhibition Of Gsdmd Accumulation In Endoplasmic Reticulum Am...mentioning

confidence: 99%

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

et al. 2022

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“…Many studies have demonstrated that Txnip comprises a major tumor suppressor that inhibits the proliferation of tumor cells (31,40,43,44,45,46) were significantly increased after 12 weeks of HFD. Thus, our results suggest that Txnip deficiency can promote pancreatic β cell proliferation in HFD-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Txnip is a multifunctional protein that is ubiquitously expressed and is localized in the nucleus, mitochondria and cytoplasm. It is associated with the development of diabetes, cardiovascular disease, central nervous system diseases, cancer and other diseases (29,30,31). Recently, Txnip has been the focus of investigation due to its unique characteristic of specifically binding and regulation of Trx activity (32).…”

Section: Introductionmentioning

confidence: 99%

“…As a tumor suppressor, Txnip has been shown to be involved in cellular growth, with functions in suppressing cellular proliferation and arresting cell cycle progression (39,40). Numerous studies have demonstrated that Txnip is downregulated in various cancers and human cancer cells, such as breast cancer, stomach cancer, lung cancer, colon cancer, cervical cancer, gastrointestinal cancer, prostate cancer, cutaneous T-cell lymphoma, and adult T-cell leukemia (31,41,42,43,44,45,46). There is also increasing evidence that Txnip can inhibit the proliferation of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

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Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Lei

Chen

Wang

et al. 2022

Endocrine Connections

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Elucidating the mechanisms of regulation of β cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β cell compensatory proliferation by subjecting wild-type (WT) and Txnip knockout (KO) mice to a high fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased β cell proliferation and enhanced β mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in β cell proliferation and cell cycle regulation. Txnip knockout in HFD mice also led to activated levels of p-P13K, p-AKT, p-mTOR and p-GSK3β, suggesting that Txnip may act via PI3K/AKT signaling to suppress β cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.

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Amino acid deprivation induces TXNIP expression by NRF2 downregulation

Ahn,

Jang,

Kim

et al. 2023

IUBMB Life

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Thioredoxin‐interacting protein (TXNIP) is sensitive to oxidative stress and is involved in the pathogenesis of various metabolic, cardiovascular, and neurodegenerative disorders. Therefore, several studies have suggested that TXNIP is a promising therapeutic target for several diseases, particularly cancer and diabetes. However, the regulation of TXNIP expression under amino acid (AA)‐restricted conditions is not well understood. In the present study, we demonstrated that TXNIP expression was promoted by the deprivation of AAs, especially arginine, glutamine, lysine, and methionine, in non‐small cell lung cancer (NSCLC) cells. Interestingly, we determined that increased TXNIP expression induced by AA deprivation was associated with nuclear factor erythroid 2‐related factor 2 (NRF2) downregulation, but not with activating transcription factor 4 (ATF4) activation. Furthermore, N‐acetyl‐l‐cysteine (NAC), a scavenger of reactive oxygen species (ROS), suppressed TXNIP expression in NSCLC cells deprived of AA. Collectively, the induction of TXNIP expression by AA deprivation was mediated by ROS production, potentially through NRF2 downregulation. Our findings suggest that TXNIP expression may be associated with the redox homeostasis of AA metabolism and provide a possible rationale for a therapeutic strategy to treat cancer with AA restriction.

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Thioredoxin-Interacting Protein in Cancer and Diabetes

Cited by 32 publications

References 196 publications

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Amino acid deprivation induces TXNIP expression by NRF2 downregulation

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