TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells

Wang, Zhenyu; Zhang, Huiyuan; Shi, Minghao; Ye, Yu; Wang, Hao; Cao, Wen; Zhao, Yanling; Zhang, Hong

doi:10.1038/srep32737

Cited by 29 publications

(19 citation statements)

References 34 publications

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“…Previous reports identified TAK1 as a mediator of metastasis and bone destruction in breast cancer (Safina et al, 2008; Safina, Sotomayor, Limoge, Morrison, & Bakin, 2011; Wang et al, 2016; X. F. Wu et al, 2014).…”

Section: Resultsmentioning

confidence: 95%

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Totzke

Gurbani

Raphemot

et al. 2017

Cell Chemical Biology

112

121

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Summary Tumor necrosis factor α (TNFα) has both positive and negative roles in human disease. In certain cancers, TNFα is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNFα antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNFα-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNFα stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated TAK1 that binds within the ATP binding pocket, yet is non-competitive, and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNFα-induced cell death, with general implications for cancer and autoimmune disease treatment.

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Section: Resultsmentioning

confidence: 95%

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Totzke

Gurbani

Raphemot

et al. 2017

Cell Chemical Biology

112

121

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“…To further evaluate whether TAK1 mediated the effect of Steap3 on liver I/R injury, we blocked TAK1 activity in L02 hepatocytes using a specific TAK1 inhibitor, NG25 . Compared with dimethyl sulfoxide (DMSO), NG25 largely abolished the activation of TAK1 and downstream JNK/p38 in Steap3 overexpressed hepatocytes subjected to H/R challenge (Fig.…”

Section: Resultsmentioning

confidence: 99%

Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1

et al. 2019

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Background and Aims Hepatic ischemia‐reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six‐transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R‐induced liver damage remains largely unclear. Approach and Results In the present study, we found that Steap3 expression was significantly up‐regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3‐KO) mice, hepatocyte‐specific Steap3 transgenic (Steap3‐HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3‐KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3‐HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor‐β–activated kinase 1 (TAK1) activation and downstream c‐Jun N‐terminal kinase (JNK) and p38 signaling during hepatic I/R injury. Conclusions Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1‐dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

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“…GKT137831, a specific inhibitor of NADPH oxidase 1 (NOX1) and NOX4; and NG25, an inhibitor of TAK1 [23, 24], were used to suppress ROS generation from NOX complexes and to down-regulate production of proinflammatory cytokines, respectively. GKT137831 and NG25, simultaneously or separately, reduced the generation of ROS but not mROS after challenge with S. uberis ( P < 0.05; Fig 6A).…”

Section: Resultsmentioning

confidence: 99%

TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species

Wan

Wang

et al. 2019

Preprint

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14Mastitis caused by Streptococcus uberis is a hazardous clinical disease in dairy 15 animals. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated 16 signaling pathways in mastitis caused by S. uberis was investigated using mouse 17 models and mammary epithelial cells (MECs). We used S. uberis to infect mammary 18 glands of wild type, TLR2 / and TLR4 / mice and quantified the adaptor molecules in 19 TLR signaling pathways, proinflammatory cytokines, tissue damage and bacterial 20 count in mammary glands. When compared with TLR4 deficiency, TLR2 deficiency 21 induced more severe pathological changes through myeloid differentiation primary 22 response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In 23 MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen 24 species (mROS) to assist host control of secretion of inflammatory factors and 25 elimination of intracellular S. uberis. Our results demonstrate that TLR2-mediated 26 mROS have a significant effect on S. uberis-induced host defense responses in 27 mammary glands as well as MECs.28 29 Author summary 30 S. uberis contributes significantly to global mastitis and remains a major obstacle for 31inflammation elimination due to its ability to form persistent infection in mammary 32 tissue. The Toll-like receptor (TLR) family plays a significant role in identifying 33 infections of intracellular bacteria and further triggering inflammatory reactions in 34 immune cells. However, the detailed molecular mechanism by which TLR is regulated, 35 and whether MECs, as the main cells in mammary gland, are tightly involved in these 36 processes is poorly understood. Here, we used S. uberis to infect mammary glands of 37 wild type, TLR2 / , TLR4 / mice and MECs to assess pathogenesis, proinflammatory 38 cytokines, ROS as well as mROS levels during infection. We found that during S.uberis 39 infection, it is TLR2 deficiency that induced more severe pathological changes 40 through MyD88-mediated signaling pathways. In addition, our work demonstrates 41 that mROS mediated by TLR2 has an important role in host defense response to 42 combat S. uberis infection in mammary glands as well as MECs. 43 44 45 Mastitis is a type of inflammation mainly caused by intramammary infection and 46 causes great harm to the dairy industry [1]. Streptococcus uberis is an environmental 47 pathogen that is emerging as the most important mastitis-causing agent in some 48 regions [2]. Previous studies in our laboratory have demonstrated that persistent 49 inflammation including swelling, secretory epithelial cell degeneration, and 50 polymorphonuclear neutrophilic leukocyte (PMN) infiltration occurs in mammary 51 tissue following injection with S. uberis [3]. The inflammatory responce caused by 52 S. uberis is lighter than that caused by E. coli [3].These pathological response 53 connected with intracellular infection of S. uberis as it escaped the elimination of 54 immune cells and formed persistent infection. 55 Activation o...

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TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells

Cited by 29 publications

References 34 publications

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1

TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species

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