Dataset Information

A small molecule targeting glutathione activates Nrf2 and inhibits cancer cell growth through promoting Keap-1 S-glutathionylation and inducing apoptosis.

ABSTRACT: The level of glutathione (GSH) is increased in many cancer cells. Consuming intracellular GSH by chemical small molecules that specifically target GSH is a new strategy to treat cancer. Recently, we synthesized and proved that a new compound 2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)cyclohexa-2,5-diene-1,4-dione (PBQC) could target to and consume intracellular GSH specifically, but, it is not clear if PBQC can affect cancer cell growth and the activity of the nuclear factor-erythroid 2-related factor 2 (Nrf2) which is a key factor involved in regulation of cancer cell growth. In this study, we addressed these questions. We found that PBQC suppressed cancer cell growth through increasing the activity of Nrf2, while it did not inhibit normal vascular endothelial cell growth. Furthermore, we demonstrated that PBQC can cause Keap-1 protein S-glutathionylation and promote Nrf2 nuclear translocation as well as the expression of pro-apoptosis genes. As a result, the cancer cells underwent apoptosis. Here, we provide a new Nrf2 activator, PBQC that can promote the expressions of pro-apoptosis genes downstream Nrf2. The data suggest that PBQC is a potential lead-compound for development of new anti-cancer drugs.

SUBMITTER: Wang L

PROVIDER: S-EPMC9076930 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A small molecule targeting glutathione activates Nrf2 and inhibits cancer cell growth through promoting Keap-1 <i>S</i>-glutathionylation and inducing apoptosis.

Wang LiHong L Qu GuoJing G Gao YuanDi Y Su Le L Ye Qing Q Jiang Fan F Zhao BaoXiang B Miao JunYing J

RSC advances 20180103 2

The level of glutathione (GSH) is increased in many cancer cells. Consuming intracellular GSH by chemical small molecules that specifically target GSH is a new strategy to treat cancer. Recently, we synthesized and proved that a new compound 2-(7-(diethylamino)-2-oxo-2<i>H</i>-chromen-3-yl)cyclohexa-2,5-diene-1,4-dione (PBQC) could target to and consume intracellular GSH specifically, but, it is not clear if PBQC can affect cancer cell growth and the activity of the nuclear factor-erythroid 2-re ...[more]

PMID: 35538996

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Project description:Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. We found that the structural perturbations had minimal dominant effects on nuclear stiffness, suggesting that the muscle pathology was not accompanied by major structural disruption of the peripheral nuclear lamina. However, subtle alterations in the lamina network and subnuclear reorganization of lamins remain possible. Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. Nrf2 is normally sequestered in the cytoplasm by Keap-1. Under oxidative stress Nrf2 dissociates from Keap-1, translocates into the nucleus, and activates gene expression. Unexpectedly, biochemical analyses revealed high levels of reducing agents, indicative of reductive stress. The accumulation of cytoplasmic lamin aggregates correlated with elevated levels of the autophagy adaptor p62/SQSTM1, which also binds Keap-1, abrogating Nrf2 cytoplasmic sequestration, allowing Nrf2 nuclear translocation and target gene activation. Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis.

Dataset Information

A small molecule targeting glutathione activates Nrf2 and inhibits cancer cell growth through promoting Keap-1 S-glutathionylation and inducing apoptosis.

Publications

A small molecule targeting glutathione activates Nrf2 and inhibits cancer cell growth through promoting Keap-1 <i>S</i>-glutathionylation and inducing apoptosis.

Similar Datasets

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