High-dose copper activates p53-independent apoptosis through the induction of nucleolar stress in human cell lines

Chen, Chieh-Hsin; Chou, Yu‐Min; Yang, Yu‐Cih; Lo, Kai-Yin

doi:10.1007/s10495-021-01692-y

Cited by 14 publications

(8 citation statements)

References 55 publications

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“…A previous study has revealed that the accumulation of copper inhibits the PI3K/AKT/mTOR pathway, which activates cellular autophagy and disrupts mitochondrial dynamics ( 29 ). Moreover, a high dose of copper can activate p53-independent apoptosis through the induction of nucleolar stress in human cell lines ( 30 ), yet the role of the p53 pathway in cuproptosis remains understudied.…”

Section: Resultsmentioning

confidence: 99%

Development of a cuproptosis-related signature for prognosis prediction in lung adenocarcinoma based on WGCNA

Ling¹,

Zhang²,

Fang³

et al. 2023

Transl Lung Cancer Res

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Background: Cuproptosis is a novel mitochondrial respiration-dependent cell death mechanism induced by copper that can kill cancer cells via copper carriers in cancer therapy. However, the clinical significance and prognostic value of cuproptosis in lung adenocarcinoma (LUAD) remains unclear.Methods: We performed a comprehensive bioinformatics analysis of the cuproptosis gene set, including copy number aberration, single-nucleotide variation, clinical characteristics, survival analysis, etc.Cuproptosis-related gene set enrichment scores (cuproptosis Z-scores) were calculated in The Cancer Genome Atlas (TCGA)-LUAD cohort using single-sample gene set enrichment analysis (ssGSEA). Modules significantly associated with cuproptosis Z-scores were screened by weighted gene co-expression network analysis (WGCNA). The hub genes of the module were then further screened by survival analysis and least absolute shrinkage and selection operator (LASSO) analysis, in which TCGA-LUAD (497 samples) and GSE72094 (442 samples) were used as the training and validation cohorts, respectively. Finally, we analyzed the tumor characteristics, immune cell infiltration levels, and potential therapeutic agents.Results: Missense mutation and copy number variant (CNV) events were general in the cuproptosis gene set. We identified 32 modules, of which the MEpurple (107 genes) and MEpink (131 genes) modules significantly positively and negatively correlated with cuproptosis Z-scores, respectively. We identified 35 hub genes significantly related to overall survival and constructed a prognostic model consisting of 7 cuproptosisrelated genes in patients with LUAD. Compared with the low-risk group, patients in the high-risk group had a worse overall survival and gene mutation frequency, as well as significantly higher tumor purity. In addition, infiltration of immune cells was also significantly different between the 2 groups. Furthermore, the correlation between the risk scores and half-maximum inhibitory concentration (IC50) of antitumor drugs in the Genomics of Drug Sensitivity in Cancer (GDSC) v. 2 database was explored, revealing differences in drug sensitivity across the 2 risk groups.Conclusions: Our study provided a valid prognostic risk model for LUAD and improved understanding of its heterogeneity, which may aid in the development of personalized treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Development of a cuproptosis-related signature for prognosis prediction in lung adenocarcinoma based on WGCNA

Ling¹,

Zhang²,

Fang³

et al. 2023

Transl Lung Cancer Res

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“…It has been proved that the cytotoxicity caused by the imbalance of copper homeostasis leads to a variety of inflammation-related biological processes, such as apoptosis and oxidative stress ( Chen et al, 2021 ). Quantitative analysis of ESTIMATE revealed obvious differences in the composition of TME between the two patterns, and C2 possessed the lowest immune score and highest tumor purity ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…The reversal of drug resistance of copper ions and copper compounds to cancer may involve the remodeling of the immune system ( Valente et al, 2021 ). The molecular mechanisms of the cell damage caused by copper, such as oxidative stress, have a significant immune correlation ( Khansari et al, 2009 ; Jomova and Valko, 2011 ; Chen et al, 2021 ). The E2F family plays a key role in the regulation of periods in cell division ( Kent and Leone, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Copper ionophore and copper chelator are considered anticancer agents ( Hu et al, 2021a ; Guo et al, 2021 ; Jiang et al, 2022 ). Initially, this copper-induced cell death was considered apoptosis ( Bhatt et al, 2021 ; Chen et al, 2021 ). However, the latest research shows that copper ionophore induces a particular form of programmed cell death, which is called cuproptosis ( Tsvetkov et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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A cuproptosis-related lncRNA signature identified prognosis and tumour immune microenvironment in kidney renal clear cell carcinoma

Sheng

Mao²,

Cui³

et al. 2022

Front. Mol. Biosci.

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Kidney renal clear cell carcinoma (KIRC) is a heterogeneous malignant tumor with high incidence, metastasis, and mortality. The imbalance of copper homeostasis can produce cytotoxicity and cause cell damage. At the same time, copper can also induce tumor cell death and inhibit tumor transformation. The latest research found that this copper-induced cell death is different from the known cell death pathway, so it is defined as cuproptosis. We included 539 KIRC samples and 72 normal tissues from the Cancer Genome Atlas (TCGA) in our study. After identifying long non-coding RNAs (lncRNAs) significantly associated with cuproptosis, we clustered 526 KIRC samples based on the prognostic lncRNAs and obtained two different patterns (Cuproptosis.C1 and C2). C1 indicated an obviously worse prognostic outcome and possessed a higher immune score and immune cell infiltration level. Moreover, a prognosis signature (CRGscore) was constructed to effectively and accurately evaluate the overall survival (OS) of KIRC patients. There were significant differences in tumor immune microenvironment (TIME) and tumor mutation burden (TMB) between CRGscore-defined groups. CRGscore also has the potential to predict medicine efficacy.

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“…Excessive copper intake can cause undesired modulation of the immune response [ 7 ]. Chen et al [ 8 ] showed that prolonged exposure of cells and tissues to excessive copper levels could activate p53-dependent or p53-independent pathways that lead to “programmed cell death” or “apoptosis”. Copper-induced “apoptosis” has been verified in spleen cells, thymocytes, and hepatocytes [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics-Based Analysis of Key Genes in Steroid-Induced Osteonecrosis of the Femoral Head That Are Associated with Copper Metabolism

Cai

et al. 2023

Biomedicines

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Osteonecrosis of the femoral head (ONFH) is a common disabling disease. Copper has positive effects on cells that regulate bone metabolism. However, the relationship between copper metabolism (CM) and steroid-induced ONFH (SONFH) remains unclear. The GSE123568 dataset was downloaded from the Gene Expression Omnibus. The differentially expressed CM-related SONFH genes (DE-CMR-SONFHGs) were identified via differential analysis and weighted gene coexpression network analysis (WGCNA). Receiver operating characteristic (ROC) analysis was performed for the predictive accuracy of key genes. Targeting drugs and the copper death-related genes (CDRGs) relevant to key genes were investigated. The bioinformatics results were confirmed via quantitative real-time polymerase chain reaction (qRT–PCR) and Western blot (WB) analysis. Two out of 106 DE-CMR-SONFHGs were identified as key genes (PNP and SLC2A1), which had diagnostic value in distinguishing SONFH from control samples and were related to various immune cell infiltrations. Eleven PMP-targeting drugs and five SLC2A1-targeting drugs were identified. The qRT–PCR, as well as WB, results confirmed the downregulation PNP and SLC2A1 and high expression of the CDRGs DLD, PDHB, and MTF1, which are closely related to these two key genes. In conclusion, PNP and SLC2A1 were identified as key genes related to SONFH and may provide insights for SONFH treatment.

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High-dose copper activates p53-independent apoptosis through the induction of nucleolar stress in human cell lines

Cited by 14 publications

References 55 publications

Development of a cuproptosis-related signature for prognosis prediction in lung adenocarcinoma based on WGCNA

Development of a cuproptosis-related signature for prognosis prediction in lung adenocarcinoma based on WGCNA

A cuproptosis-related lncRNA signature identified prognosis and tumour immune microenvironment in kidney renal clear cell carcinoma

Bioinformatics-Based Analysis of Key Genes in Steroid-Induced Osteonecrosis of the Femoral Head That Are Associated with Copper Metabolism

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