A critical role of the thioredoxin domain containing protein 5 (TXNDC5) in redox homeostasis and cancer development

Chawsheen, Hedy A.; Ying, Qi; Jiang, Hong; Wei, Qiou

doi:10.1016/j.gendis.2018.09.003

Cited by 37 publications

(22 citation statements)

References 70 publications

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“…3 and 4). Previous studies in RMS and other cancer cell lines (34)(35)(36)(37) show that NR4A1 regulates expression of TXNDC5 and IDH1, which help to maintain cellular reductant levels (49,50). In RMS cells, transfection with siNR4A1 or treatment with DIM-C-pPhOH decreased TXNDC5 and IDH1 expression and the responses observed were duplicated in separate experiments where TXNDC5 and IDH1 were silenced by RNAi (Figs.…”

Section: Discussionmentioning

confidence: 66%

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

Hedrick

Mohankumar

Lacey

et al. 2019

Molecular Cancer Research

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Nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in rhabdomyosarcoma (RMS), and inactivation of NR4A1 (siNR4A1) or treatment with the NR4A1 antagonist 1,1-bis (3 0 -indoly)-1-(p-hydroxy-phenyl)methane (DIM-C-pPhOH) has antiproliferative and proapoptotic effects on RMS cells. However, the mechanism by which NR4A1 inhibition exerts these effects is poorly defined. Here, we report that NR4A1 silencing or inhibition resulted in accumulation of reactive oxygen species (ROS) and ROS-dependent induction of the tumor suppressor-like cytokine IL24 in RMS cells. Mechanistically, NR4A1 was found to regulate the expression of the proreductant genes thioredoxin domain-containing 5 (TXNDC5) and isocitrate dehydrogenase 1 (IDH1), which are downregulated in RMS cells following NR4A1 knockdown or inhibition. Silencing TXNDC5 and IDH1 also induced ROS accumulation and IL24 expression in RMS cells, suggesting that NR4A1 antagonists mediate their antiproliferative and apoptotic effects through modulation of proreductant gene expression. Finally, cotreatment with the antioxidant glutathione or IL24-blocking antibody reversed the effects of NR4A1 inhibition, demonstrating the importance of both ROS and IL24 in mediating the cellular responses.Implications: Overall, these data elucidate the mechanism by which NR4A1 inhibition functions to inhibit the proliferation, survival, and migration of RMS cells.

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Section: Discussionmentioning

confidence: 66%

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

Hedrick

Mohankumar

Lacey

et al. 2019

Molecular Cancer Research

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“…Although PDI proteins are recognised as one of the most abundant cellular proteins, they are frequently upregulated in a variety of cancer types. Microarray data analysis has demonstrated the upregulation of several typical PDI members including PDIA1, PDIA3, PDIA4 and PDIA6 in multiple cancers such as breast, colorectal, liver, brain and prostate 10 . This is demonstrated in gene expression data attained from the Gene Expression Atlas datasets 13 .…”

Section: Pdi In Cancermentioning

confidence: 91%

Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy

Powell

Foster

2021

Cancer Medicine

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The protein disulphide isomerase (PDI) gene family is a large, diverse group of enzymes recognised for their roles in disulphide bond formation within the endoplasmic reticulum (ER). PDI therefore plays an important role in ER proteostasis, however, it also shows involvement in ER stress, a characteristic recognised in multiple disease states, including cancer. While the exact mechanisms by which PDI contributes to tumorigenesis are still not fully understood, PDI exhibits clear involvement in the unfolded protein response (UPR) pathway. The UPR acts to alleviate ER stress through the activation of ER chaperones, such as PDI, which act to refold misfolded proteins, promoting cell survival. PDI also acts as an upstream regulator of the UPR pathway, through redox regulation of UPR stress receptors. This demonstrates the pro‐protective roles of PDI and highlights PDI as a potential therapeutic target for cancer treatment. Recent research has explored the use of PDI inhibitors with PACMA 31 in particular, demonstrating promising anti‐cancer effects in ovarian cancer. This review discusses the properties and functions of PDI family members and focuses on their potential as a therapeutic target for cancer treatment.

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“…[ 28 ] The over‐expression of TXNDC5 is closely related to the elevated level of oxidative stress and hypoxia, which further promotes the invasion and metastasis of cancer cells. [ 29 ] PTT typically results in excess production of inflammatory factors and exacerbates the hypoxia tumor microenvironment, further promoting the upregulation of TXNDC5 expression. [ 30 ]…”

Section: Resultsmentioning

confidence: 99%

CRISPR/Cas9‐2D Silicene Gene‐Editing Nanosystem for Remote NIR‐II‐Induced Tumor Microenvironment Reprogramming and Augmented Photonic Tumor Ablation

Yin

Zhou

Dong

et al. 2021

Adv Funct Materials

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Photothermal therapy (PTT) is a minimally invasive and highly specific antineoplastic treatment, whereas the significant upregulation of TXNDC5 gene expression following PTT cripples the photothermal ablation efficacy through protein processing in the endoplasmic reticulum signaling pathway, as transcriptome sequencing and bioinformatics analysis revealed in this research. To tackle this crucial issue, a second near-infrared biowindow (NIR-II) light-controlled CRISPR/Cas9 nanosystem (silicene-Cas9) is constructed based on biosafe and biodegradable 2D silicene nanosheets with desirable photothermal-conversion capability. The elaborate system enables remote NIR-II-induced reprogramming of tumor microenvironment for enhanced photonic tumor ablation. Moreover, this CRISPR/Cas9 delivery system is carried out to precisely and efficiently knock down TXNDC5 for reprogramming the tumor microenvironment and amplifying the photothermal performance of silicene, exhibiting high efficiency and controlled gene-editing capacity of 47.68% and significantly improving therapeutic effect of tumor ablation without recurrence both in vitro and in vivo. This work not only provides a paradigm of improving the effectiveness of photothermal tumor therapy, but also develops a safe and efficient 2D silicene-based nonviral vector for harnessing CRISPSR/Cas9 technology-mediated genome editing, which further broadens the biomedical application of 2D silicene nanosheets.

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A critical role of the thioredoxin domain containing protein 5 (TXNDC5) in redox homeostasis and cancer development

Cited by 37 publications

References 70 publications

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy

CRISPR/Cas9‐2D Silicene Gene‐Editing Nanosystem for Remote NIR‐II‐Induced Tumor Microenvironment Reprogramming and Augmented Photonic Tumor Ablation

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