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ARMS-NF-κB signaling regulates intracellular ROS to induce autophagy-associated cell death upon oxidative stress.

ABSTRACT: Ankyrin repeat-rich membrane spanning (ARMS) plays roles in neural development, neuropathies, and tumor formation. Such pleiotropic function of ARMS is often attributed to diverse ARMS-interacting molecules in different cell context. However, it might be achieved by ARMS' effect on global biological mediator like reactive oxygen species (ROS). We established ARMS-knockdown in melanoma cells (siARMS) and in Drosophila eyes (GMR>dARMS ^RNAi ) and challenged them with H₂O₂. Decreased ARMS in both systems compromises nuclear translocation of NF-κB and induces ROS, which in turn augments autophagy flux and confers susceptibility to H₂O₂-triggered autophagic cell death. Resuming NF-κB activity or reducing ROS by antioxidants in siARMS cells and GMR>dARMS ^RNAi fly decreases intracellular peroxides level concurrent with reduced autophagy and attenuated cell death. Conversely, blocking NF-κB activity in wild-type flies/melanoma enhances ROS and induces autophagy with cell death. We thus uncover intracellular ROS modulated by ARMS-NFκB signaling primes autophagy for autophagic cell death upon oxidative stress.

SUBMITTER: Liao YH

PROVIDER: S-EPMC9926119 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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ARMS-NF-κB signaling regulates intracellular ROS to induce autophagy-associated cell death upon oxidative stress.

Liao Yi-Hua YH Wu June-Tai JT Hsieh I-Chun IC Lee Hsiu-Hsiang HH Huang Pei-Hsin PH

iScience 20230118 2

Ankyrin repeat-rich membrane spanning (ARMS) plays roles in neural development, neuropathies, and tumor formation. Such pleiotropic function of ARMS is often attributed to diverse ARMS-interacting molecules in different cell context. However, it might be achieved by ARMS' effect on global biological mediator like reactive oxygen species (ROS). We established ARMS-knockdown in melanoma cells (siARMS) and in Drosophila eyes (GMR>dARMS RNAi ) and challe ...[more]

PMID: 36798436

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Project description:BackgroundThe incidence of ovarian cancer ranks third among female gynecological cancers in the world, and more than 90% of patients are epithelial ovarian cancer (EOC). Carboplatin is the first-line chemotherapy drug for the treatment of EOC patients. However, patients who are resistant to carboplatin often do not benefit from it. Therefore, finding a key molecule that affects carboplatin sensitivity is expected to enhance the efficacy of carboplatin in EOC treatment.MethodsThe human EOC cell line SK-OV-3 and TOV-21G were used in this study. The second-generation sequencing technology was used to sequence the transcripts of carboplatin-resistant EOC cells and parental EOC cells. The bioinformatic analysis of the differentially expressed genes was performed by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The EOC tissue chip in the Gene Expression Omnibus (GEO) database was also analyzed to screen the target gene. Flow cytometry, Hoechst staining, Western blot, MTS, mitochondrial specific reducing agent (Mito Tempo), and nuclear factor kappa-B (NF-κB) pathway inhibitor (BAY 11-7082) were used to explore the effect of proteasome 26S subunit, non-ATPase 4 (PSMD4) on the autophagy, apoptosis, and reactive oxygen species (ROS) accumulation of carboplatin-resistant EOC cells treated with carboplatin. In vivo, the carboplatin-resistant EOC cell lines treated with PSMD4 knockdown were injected subcutaneously into mice (twelve female BALB/c nude mice) to construct EOC subcutaneous xenograft tumor models.ResultsBased on second-generation sequencing technology and bioinformatics analysis, it was found that PSMD4 is the core molecule in the carboplatin resistance regulatory network in EOC, and its expression is up-regulated in EOC carboplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the down-regulated expression of PSMD4 is closely related to the increase in sensitivity of EOC to carboplatin. Mechanically, we found that inhibiting PSMD4 expression may inhibit the activation of the NF-κB pathway, promote carboplatin-induced ROS accumulation in EOC cells, inhibit EOC cell autophagy, and enhance the sensitivity of EOC to carboplatin.ConclusionsDown-regulation of PSMD4 may inhibit the activation of the NF-κB pathway and autophagy, and up-regulate the level of intracellular ROS accumulation, thereby promoting carboplatin-mediated EOC cell apoptosis and enhancing carboplatin sensitivity.

Dataset Information

ARMS-NF-κB signaling regulates intracellular ROS to induce autophagy-associated cell death upon oxidative stress.

Publications

ARMS-NF-κB signaling regulates intracellular ROS to induce autophagy-associated cell death upon oxidative stress.

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