Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Tsvetkov, Peter; Detappe, Alexandre; Cai, Kezhou; Hr, Keys; Brune, Zarina; Ying, Weiwen; Thiru, Prathapan; Reidy, Mairéad; Kugener, Guillaume; Tsherniak, Aviad; Santagata, Sandro; Whitesell, Luke; Jl, Markley; Ghobrial, IM; Lindquist, Susan

doi:10.1101/288365

Cited by 26 publications

(36 citation statements)

References 88 publications

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“…FDX1 encodes a small iron-sulfur protein that participates in the reduction in mitochondrial cytochrome and the synthesis of various steroid hormones (Sheftel et al, 2010;Strushkevich et al, 2011). Also, FDX1 can augment the copper-dependent cell death induced by elesclomol and may provide a new idea for increasing the efficacy of several cancer-targeting agents (Tsvetkov et al, 2019). Next, we focused on FDX1 and explored its function in LUAD.…”

Section: Resultsmentioning

confidence: 99%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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Background: Lung cancer has emerged as one of the most common cancers in recent years. The mitochondrial electron transport chain (ETC) is closely connected with metabolic pathways and inflammatory response. However, the influence of ETC-associated genes on the tumor immune response and the pathogenesis of lung cancer is not clear and needs further exploration.Methods: The RNA-sequencing transcriptome and clinical characteristic data of LUAD were downloaded from the Cancer Genome Atlas (TCGA) database. The LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve. We explored the function of FDX1 through flow cytometry, molecular biological methods, and liquid chromatography–tandem mass spectrometry/mass spectrometry (LC–MS/MS).Results: 12 genes (FDX1, FDX2, LOXL2, ASPH, GLRX2, ALDH2, CYCS, AKR1A1, MAOB, RDH16, CYBB, and CYB5A) were selected to build the risk signature, and the risk score was calculated with the coefficients from the LASSO algorithm. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves of the dataset were 0.7, 0.674, and 0.692, respectively. Univariate Cox analysis and multivariate Cox regression analysis indicated that the risk signature is an independent risk factor for LUAD patients. Among these genes, we focused on the FDX1 gene, and we found that knockdown of FDX1 neither inhibited tumor cell growth nor did it induce apoptosis or abnormal cell cycle distribution. But FDX1 could promote the ATP production. Furthermore, our study showed that FDX1 was closely related to the glucose metabolism, fatty acid oxidation, and amino acid metabolism.Conclusion: Collectively, this study provides new clues about carcinogenesis induced by ETC-associated genes in LUAD and paves the way for finding potential targets of LUAD.

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Section: Resultsmentioning

confidence: 99%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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“…In addition, in terms of tumor chemotherapy, there were few studies on the relationship between FDX1 and tumor resistance. Only Tsvetkov et al (Tsvetkov et al, 2019) found that FDX1 was highly associated with the proteasome inhibitor elesclomol and a direct target of elesclomol. However, no correlation was found between the two in our study, which might be related to the low number of cell lines in the CellMiner database and the slow update of experimental data.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker

Zhang

Zeng²,

Guo³

et al. 2022

Front. Genet.

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Background: The latest research identified cuproptosis as an entirely new mechanism of cell death. However, as a key regulator in copper-induced cell death, the prognostic and immunotherapeutic value of FDX1 in pan-cancer remains unclear.Methods: Data from the UCSC Xena, GEPIA, and CPTAC were analyzed to conduct an inquiry into the overall differential expression of FDX1 across multiple cancer types. The expression of FDX1 in GBM, LUAD and HCC cell lines as well as their control cell lines was verified by RT-QPCR. The survival prognosis, clinical features, and genetic changes of FDX1 were also evaluated. Finally, the relationship between FDX1 and immunotherapy response was further explored through Gene Set Enrichment Analysis enrichment analysis, tumor microenvironment, immune cell infiltration, immune gene co-expression and drug sensitivity analysis.Results: The transcription and protein expression of FDX1 were significantly reduced in most cancer types and had prognostic value for the survival of certain cancer patients such as ACC, KIRC, HNSC, THCA and LGG. In some cancer types, FDX1 expression was also markedly correlated with the clinical characteristics, TMB, MSI, and antitumor drug susceptibility or resistance of different tumors. Gene set enrichment analysis showed that FDX1 was significantly associated with immune-related pathways. Moreover, the expression level of FDX1 was confirmed to be strongly correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes to a certain extent.Conclusion: This study comprehensively explored the potential value of FDX1 as a prognostic and immunotherapeutic marker for pan-cancer, providing new direction and evidence for cancer therapy.

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“…A previous study found that copper commonly exhibited anti-tumor effects via the formation of metal chelators and ionophores (Steinbrueck et al, 2020). For the first time, Tsvetkov et al defined Cudependent cytotoxicity, which leads to regulated cell death (RCD), as "cuproptosis" (Tsvetkov et al, 2019;Tsvetkov et al, 2022). Previous research suggested that copper-dependent cell death was correlated with the progression and treatment of glioma (Buccarelli et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A cuproptosis-related lncRNAs signature for prognosis, chemotherapy, and immune checkpoint blockade therapy of low-grade glioma

Yan

Wang²,

Dong³

et al. 2022

Front. Mol. Biosci.

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Cuproptosis is a new type of cell death that is associated with mitochondrial respiration of the tricarboxylic acid cycle. Previous studies showed that long non-coding RNAs (lncRNAs) regulated low-grade glioma (LGG) progression. However, the potential applications of cuproptosis-related lncRNAs (CRLs) in LGG were not explored. A comprehensive analysis was performed in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts. We first screened two distinct cuproptosis subtypes based on prognostic CRLs using consensus clustering. To facilitate individualized survival prediction in LGG, we constructed a prognostic signature (including CRNDE, HAR1A, and FAM181A-AS1) in the TCGA dataset. The prognostic signature exhibited excellent predictive ability and reliability, which was validated in the CGGA_325 and CGGA_693 datasets. Notably, patients in the high-risk group had increased immune cell infiltration and expression of immune checkpoints, which indicated that they may benefit more from immune checkpoint blockade (ICB) therapy. Finally, the prognostic signature screened the population with sensitivity to chemotherapy and ICB therapy. In summary, this study initially explored the mechanism of CRLs in LGG and provides some insights into chemotherapy and ICB therapy of LGG.

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Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Cited by 26 publications

References 88 publications

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker

A cuproptosis-related lncRNAs signature for prognosis, chemotherapy, and immune checkpoint blockade therapy of low-grade glioma

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