Optimization of novel oxidative DIMs as Nur77 modulators of the Nur77-Bcl-2 apoptotic pathway

Tu, Xuhuang; Chen, Xiaohui; Zhang, Dongliang; Gao, Meichun; Liang, Junmin; Bao, Guoliang; Zhang, Jie; Peng, Shuangzhou; Zhang, Xiaokun; Zeng, Zhiping; Su, Ying

doi:10.1016/j.ejmech.2020.113020

Cited by 9 publications

(5 citation statements)

References 45 publications

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“…While, Nur77 exerts pro-apoptotic effects when it is translocated into the mitochondria. Nur77 disables Bcl2 in the mitochondria to disrupt the outer mitochondrial membrane, leading to the generation of ROS generation and apoptosis [53]. Our data indicate that Nur77 is strongly up-regulated in cisplatin-induced AKI (Fig.…”

Section: Discussionmentioning

confidence: 57%

CHIP Drives Proteasomal Degradation of Nur77 to Alleviate Oxidative Stress and Intrinsic Apoptosis in Cisplatin-induced Nephropathy

Zhang,

Deng,

Wang

et al. 2023

Preprint

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Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrate that CHIP is abundantly expressed in the renal proximal tubular epithelia, and its expression is downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated Nur77 to promote its degradation, which consequently shielded Bcl2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrate that CHIP interacts with Nur77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicate that CHIP ubiquitinates and degrades its substrate Nur77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI.

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Section: Discussionmentioning

confidence: 57%

CHIP Drives Proteasomal Degradation of Nur77 to Alleviate Oxidative Stress and Intrinsic Apoptosis in Cisplatin-induced Nephropathy

Zhang,

Deng,

Wang

et al. 2023

Preprint

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“…Nur77 translocating from the nucleus to mitochondria and its subsequent interaction with Bcl-2 can convert Bcl-2 from a survival to a killer of tumor cells 11 , 12 , representing a promising strategy to develop new cancer therapeutics 9 , 44 . Although several small molecules that bind Nur77 to trigger Nur77-dependent apoptosis have been identified, their efficacy and selectivity remain to be improved 30 , 45 , 46 , 47 . Given that Nur77 lacks classical LBP 34 , 48 , the search for small molecules that specifically bind to Nur77 to activate its apoptotic pathway remains a great challenge.…”

Section: Discussionmentioning

confidence: 99%

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

Chen,

Gao,

Xia

et al. 2024

Acta Pharmaceutica Sinica B

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“…Increasing evidence indicates that subcellular localization, specifically nucleus versus mitochondria, regulates Nur77 function (Medzikovic et al, 2019). It was reported that Nur77 upon proapoptotic stimulation translocated to the mitochondria triggering cytochrome c release and apoptosis (Tu et al, 2021). Phosphorylation of Nur77 by kinases was required for its passing from nucleus to cytoplasm (Chen et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)‐mediated epigenetic regulation of glutaminase 1

Chen

Liang

Xia

et al. 2023

British J Pharmacology

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Background and PurposeSenescence in hepatic stellate cells (HSCs) limits liver fibrosis. Glutaminolysis promotes HSC activation. Here, we investigated how emodin affected HSC senescence involving glutaminolysis.Experimental ApproachSenescence, glutaminolysis metabolites, Nur77 nuclear translocation, glutaminase 1 (GLS1) promoter methylation and related signalling pathways were examined in human HSC‐LX2 cells using multiple cellular and molecular approaches. Fibrotic mice with shRNA‐mediated knockdown of Nur77 were treated with emodin‐vitamin A liposome for investigating the mechanisms in vivo. Human fibrotic liver samples were examined to verify the clinical relevance.Key ResultsEmodin upregulated several key markers of senescence and inhibited glutaminolysis cascade in HSCs. Emodin promoted Nur77 nuclear translocation, and knockdown of Nur77 abolished emodin blockade of glutaminolysis and induction of HSC senescence. Mechanistically, emodin facilitated Nur77/DNMT3b interaction and increased GLS1 promoter methylation, leading to inhibited GLS1 expression and blockade of glutaminolysis. Moreover, the glutaminolysis intermediate α‐ketoglutarate promoted extracellular signal‐regulated kinase (ERK) phosphorylation, which in turn phosphorylated Nur77 and reduced its interaction with DNMT3b. This led to decreased GLS1 promoter methylation and increased GLS1 expression, forming an ERK/Nur77/glutaminolysis positive feedback loop. However, emodin repressed ERK phosphorylation and interrupted the feedback cascade, stimulating senescence in HSCs. Studies in mice showed that emodin‐vitamin A liposome inhibited glutaminolysis and induced senescence in HSCs, and consequently alleviated liver fibrosis; but knockdown of Nur77 abrogated these beneficial effects. Similar alterations were validated in human fibrotic liver tissues.Conclusions and ImplicationsEmodin stimulated HSC senescence through interruption of glutaminolysis. HSC‐targeted delivery of emodin represented a therapeutic option for liver fibrosis.

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Optimization of novel oxidative DIMs as Nur77 modulators of the Nur77-Bcl-2 apoptotic pathway

Cited by 9 publications

References 45 publications

CHIP Drives Proteasomal Degradation of Nur77 to Alleviate Oxidative Stress and Intrinsic Apoptosis in Cisplatin-induced Nephropathy

CHIP Drives Proteasomal Degradation of Nur77 to Alleviate Oxidative Stress and Intrinsic Apoptosis in Cisplatin-induced Nephropathy

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)‐mediated epigenetic regulation of glutaminase 1

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