EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis

Fan, Chi-Chen; Tsai, Sheng-Ta; Lin, Chen‐Yuan; Chang, Ling‐Chu; Yang, Juan-Cheng; Chen, Guan‐Yu; Sher, Yuh‐Pyng; Wang, Shao‐Chun; Hsiao, Michael; Chang, Wei‐Chao

doi:10.1016/j.redox.2020.101571

Cited by 42 publications

(28 citation statements)

References 61 publications

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“…ABCC1 multidrug resistance protein (1/MRP1) is a member of the C subfamily of ABC transporters that is capable of contributing to chemotherapeutic failure in various cancers by regulating the efflux of chemotherapeutic drugs ( Sharom, 2008 ; Robey et al, 2018 ). Previous reports have shown that ABCC1 is a negative biomarker associated with a decreased survival rate and an increased risk of relapse in colorectal cancer ( Zhao et al, 2020 ), lung cancer ( Fan et al, 2020 ), and breast cancer ( Low et al, 2020 ). However, the relationship with UVM has not been investigated in detail.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma

Jin

Wang

et al. 2021

Front. Cell Dev. Biol.

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Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.

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Section: Discussionmentioning

confidence: 99%

Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma

Jin

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…It has been reported that EF hand domain-containing protein 2 (EFHD2) as a calcium-binding protein enhances production of NOX4 to promote ROS generation. Subsequently, ROS generation function as upstream mediator of ABCB1 to enhance its expression, resulting in CP resistance [132].…”

Section: Cisplatin Resistancementioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

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“…Lung adenocarcinoma is a common pathological type of lung cancer. NOX4 is typically highly expressed in lung epithelial cells and affects cell migration and fibronectin expression, causing poor prognosis (Fan et al, 2020). The NOX4 gene is a target of miR‐99a (Yin et al, 2018).…”

Section: The Roles Of Nox4 In Respiratory System Diseasesmentioning

confidence: 99%

The role of NOX4 in pulmonary diseases

Feng

et al. 2020

Journal Cellular Physiology

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Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a subtype of the NOX family, which is mainly expressed in the pulmonary vasculature and pulmonary endothelial cells in the respiratory system. NOX4 has unique characteristics, and is a constitutively active enzyme that primarily produces hydrogen peroxide. The signaling pathways associated with NOX4 are complicated. Negative and positive feedback play significant roles in regulating NOX4 expression. The role of NOX4 is controversial because NOX4 plays a protective or damaging role in different respiratory diseases. This review summarizes the structure, enzymatic properties, regulation, and signaling pathways of NOX4. This review then introduces the roles of NOX4 in different diseases in the respiratory system, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis

Cited by 42 publications

References 61 publications

Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma

Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

The role of NOX4 in pulmonary diseases

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