APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations

Hong, Yuheng; Ren, Tianyuan; Wang, Xiaoxuan; Liu, Xia; Fei, Yue; Meng, Shen; Han, Xu; Sun, Cong; Shen, Hongru; Li, Lanfang; Qiu, Lihua; Zhou, Qian; Zhou, Shunhua; Zhang, Huilai; Li, Linyu

doi:10.1038/s41375-022-01634-w

Cited by 37 publications

(28 citation statements)

References 50 publications

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“…Due to their exaggerated metabolic characteristics, most tumors are in a high oxidative-stress state, and these tumors (such as hepatocellular carcinoma [48], osteosarcoma [49], prostate cancer [50], cervical cancer [51], and diffuse large B cell lymphoma [52]) are more vulnerable to ferroptosis. Investigators recently demonstrated that iron metabolism is dramatically perturbed in a number of cancers that include breast cancer [53], glioblastoma [54], prostate cancer [55], and OV [56], and are characterized by the upregulation of the iron importer TFR1 and iron-storage protein ferritin and the downregulation of the iron efflux pump FPN.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression and Clinical Significance of a Ferroptosis-Related Genome in Ovarian Serous Cystadenocarcinoma: A Study Based on TCGA Data

Yang¹

2022

Oncologie

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Background: Epithelial ovarian cancer (EOC) is the deadliest malignancy among the gynecologic tumors, and ovarian serous cystadenocarcinoma (OV) is the dominant histological type. Ferroptosis is a novel iron-dependent, programmed form of cell death, and agents that trigger ferroptosis may constitute potential anti-cancer therapies. Materials and Methods: We herein extracted the genes that participate in the process of ferroptosis from the online FerrDb database to create a ferroptosis-related genome (FRG), and then comprehensively analyzed the relationship between the mRNA expression of each gene and the clinicopathologic features of The Cancer Genome Atlas (TCGA)-OV cohort. Results: We found that most of the FRG genes were differently expressed between OV and normal ovarian tissue and were significantly related to the prognosis of OV. In addition, gene ontology (GO) analysis revealed that the candidate genes of the FRG were primarily associated with responses to nutrient levels, oxidative stress, oxygen levels, and neuronal death. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that candidate genes of the FRG were primarily associated with ferroptosis, hepatitis B, mitophagy, prostate cancer, and bladder cancer. The protein-protein interaction (PPI) network exhibited 132 nodes, 565 edges, an average node degree of 9.94, and an average local clustering coefficient of 0.539, indicating that the proteins were closely interrelated with one another and constitute a biological cluster. A comprehensive analysis of the top 5 genes involved in promoting and preventing ferroptosis revealed that these genes were differently expressed between OV and normal ovarian tissue, were significantly related to the prognosis of OV, reflected excellent diagnostic value, and were significantly correlated with immune cell infiltration in the tumor microenvironment (TME), polarization of macrophages, and with immune checkpoints. The protein levels of top 5 genes involved in promoting ferroptosis were differentially expressed between OV and normal ovarian tissue, and the top 5 genes involved in preventing ferroptosis were constitutively expressed in most of the normal tissues and tumors. Conclusions: We herein ascertained that the majority of the FRG was differentially expressed between OV and normal ovarian tissue, that the genes were significantly related to prognosis, and that the dysregulation of ferroptosis appeared to influence the development and progression of OV. The FRG showed an excellent diagnostic value for OV, and we postulate that it is significantly correlated with immune cell infiltration and immune checkpoints in the TME. We posit that targeting ferroptosis might comprise a novel anti-cancer therapy in OV.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression and Clinical Significance of a Ferroptosis-Related Genome in Ovarian Serous Cystadenocarcinoma: A Study Based on TCGA Data

Yang¹

2022

Oncologie

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“…It has also been found that mut-p53 may make PDAC cells prone to ferroptosis by reducing the expression of ferritin heavy chain 1 (FTH1)/ nuclear receptor coactivator 4 (NCOA4) (77). Eprenetapopt (APR-246) is a compound to shift mutant p53 and induces ferroptosis in DLBCL cells carrying wt-p53 and other forms of TP53 mutations (78). Meanwhile, it has been found that heat stress can also induce the accumulation of p53 protein.…”

Section: Mwa Might Regulate the Ferroptosis Of Cancer Cells By Induce...mentioning

confidence: 99%

Crosstalk between microwave ablation and ferroptosis: The next hot topic?

et al. 2023

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Microwave ablation has been one form of thermal ablation in treatments for many tumors, which can locally control unresectable tumors. Ferroptosis is iron-dependent cell death caused by the cumulative reactive oxygen species and lipid peroxidation products. Recently, increasing evidence has shown that ferroptosis might play a vital role in MWA-induced tumor suppression. In this article, we briefly illustrate the concept of ferroptosis, the related signal pathways and inducers, the basic principle of microwave ablation in killing tumors, and the key molecules released after microwave ablation. Then, we describe the cross-talking molecules between microwave ablation and ferroptosis, and discussed the potential mechanism of microwave ablation-induced ferroptosis. This review explores the therapeutic target of ferroptosis in enhancing the systemic antitumor effect after microwave ablation, providing theoretical support in combinational microwave ablation with pro-ferroptosis therapy.

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“…However, there is contradictory evidence. For instance, the drug APR-246 can induce ferroptosis more efficiently in blood cancer cells with mutp53 ( Birsen et al, 2021 ; Fujihara et al, 2022 ; Hong et al, 2022 ). Although the pro-ferroptotic action of APR-246 is independent of p53 ( Liu et al, 2017 ; Magri et al, 2021 ; Fujihara et al, 2022 ), the drug is a powerful inhibitor of mutant p53 ( Hassin and Oren, 2022 ; Levine, 2022 ), and this may contribute to its efficacy.…”

Section: Ferroptosismentioning

confidence: 99%

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Corazzari

Collavin

2023

Front. Genet.

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Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.

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APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations

Cited by 37 publications

References 50 publications

Comprehensive Analysis of the Expression and Clinical Significance of a Ferroptosis-Related Genome in Ovarian Serous Cystadenocarcinoma: A Study Based on TCGA Data

Comprehensive Analysis of the Expression and Clinical Significance of a Ferroptosis-Related Genome in Ovarian Serous Cystadenocarcinoma: A Study Based on TCGA Data

Crosstalk between microwave ablation and ferroptosis: The next hot topic?

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

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