Remdesivir inhibits the progression of glioblastoma by enhancing endoplasmic reticulum stress

Chen, Yujia; Guo, Yunbo; Li, Shenglun; Xu, Jiacheng; Ning, Weihai; Zhao, Chunjiang; Wang, Jun; Qu, Yanming; Zhang, Mingshan; Zhou, Wanlu; Cui, Qinghua; Zhang, Hongwei

doi:10.1016/j.biopha.2022.114037

Cited by 5 publications

(3 citation statements)

References 50 publications

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“…We believe that RDV may upregulate hERG mRNA levels to a similar extent in both WT and mutant hERG expressing cells, the discrepancy between trafficking competent and incompetent hERG channels in responses to RDV may be a result of the different levels of ER stress induced by the differing degrees of mutant subunits in the hERG channels. In fact, RDV induced promotion of ER stress and activation of the PERK-mediated UPR has been reported in glioblastoma cells (Chen et al, 2023). Thus, WT hERG may demonstrate increased expression and function following RDV administration due to minimal ER stress, whereas heteromeric mutant hERG channels may show diminished expression and function due to enhanced ER stress-related mRNA reduction and protein degradation.…”

Section: Discussionmentioning

confidence: 94%

Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels

et al. 2023

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The human ether-a-go-go-related gene (hERG) encodes for the pore-forming subunit of the channel that conducts the rapidly activating delayed K + current (I Kr ) in the heart. The hERG channel is important for cardiac repolarization, and reduction of its expression in the plasma membrane due to mutations causes long-QT syndrome type 2 (LQT2). As such, promoting hERG membrane expression is a strategy to rescue mutant channel function. In the present study, we applied patch clamp, Western blots, immunocytochemistry, and Quantitative Reverse Transcription PCR (RT-qPCR) techniques to investigate the rescue effects of two drugs, remdesivir and lumacaftor, on trafficking defective mutant hERG channels. As our group has SIGNIFICANCE STATEMENTVarious naturally occurring mutations in a cardiac potassium channel called hERG can impair channel function by decreasing cell-surface channel expression, resulting in cardiac electrical disturbances and even sudden cardiac death. Promotion of cell-surface expression of mutant hERG channels represents a strategy to rescue channel function. This work demonstrates that drugs such as remdesivir and lumacaftor can differently affect homomeric and heteromeric mutant hERG channels, which have biological and clinical implications.

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Section: Discussionmentioning

confidence: 94%

Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels

et al. 2023

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“…This design leverages genetic variants as instrumental variables to mitigate confounding influences, thereby elucidating the causal associations inherent to this interplay. [38–40] In essence, Mendelian randomization acts as a surrogate for randomized controlled trials, offering a robust framework for assessing causality in observational data. This investigative method has proven to be instrumental in enhancing our comprehension of the intricate mechanisms whereby inflammatory processes may potentiate the development of gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Exploring the association between inflammatory biomarkers and gastric cancer development: A two-sample mendelian randomization analysis.

Yang,

Lv,

et al. 2024

Medicine

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This study aimed to elucidate the potential causative links between inflammatory biomarkers and gastric cancer risk via a two-sample Mendelian randomization approach. Leveraging genome-wide association study (GWAS) data, we conducted a two-sample Mendelian randomization analysis. Instrumental variable selection for inflammatory markers – namely, tissue factor, monocyte chemotactic protein-1, E-selectin, interleukin 6 receptor, and fatty acid-binding protein 4 – was informed by SNP data from the IEU database. Strongly associated SNPs served as instrumental variables. We applied a suite of statistical methods, including Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger, and mode-based estimates, to compute the odds ratios (ORs) that articulate the impact of these markers on gastric cancer susceptibility. The IVW method revealed that the interleukin 6 receptor was inversely correlated with gastric cancer progression (OR = 0.86, 95% CI = 0.74–0.99, P = .03), whereas fatty acid-binding protein 4 was found to elevate the risk (OR = 1.21, 95% CI = 1.05–1.39, P = .03). Instrumental variables comprised 5, 4, 7, 2, and 3 SNPs respectively. Convergent findings from WME, MR-Egger, and mode-based analyses corroborated these associations. Sensitivity checks, including heterogeneity, horizontal pleiotropy assessments, and leave-one-out diagnostics, affirmed the robustness and reliability of our instruments across diverse gastric malignancy tissues without substantial bias. Our research suggests that the interleukin 6 receptor potentially mitigates, while fatty acid-binding protein 4 may contribute to the pathogenesis of gastric cancer (GC). Unraveling the intricate biological interplay between inflammation and oncogenesis offers valuable insights for preemptive strategies and therapeutic interventions in gastric malignancy management.

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“…[6] Subsequent studies have revealed that de novo FA synthesis plays a crucial role in tumorigenesis and progression in various tumor cells, and the inhibition of de novo FA synthesis has been linked to BRCA growth suppression and improved survival rates in vivo and in vitro. [7–9]…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of fatty acid desaturases in breast invasive carcinoma: The prognosis, gene mutation, and tumor immune microenvironment

Wang,

Zhang,

Zhou

et al. 2024

Medicine

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Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA) desaturation. Stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturase 2 (FADS2) are two key rate-limiting enzymes that catalyze the FA desaturation process and cooperate to accelerate lipid metabolic activities. In this study, we investigated the potential functions of SCD and FADS2 in BRCA using bioinformatic analysis and experimental validation. The gene expression profiling interactive analysis database showed that the expression of SCD or FADS2 genes was positively linked to worse overall survival and disease-free survival in the Cancer Genome Atlas database-BRCA. The University of Alabama at Birmingham cancer data analysis portal database indicates that the expression and methylation levels of SCD or FADS2 are associated with various clinicopathological factors in patients with BRCA. Moreover, the tumor immune estimation resource and TISCH databases showed a significant positive correlation between the expression of SCD and the abundance of CD8+ T cells and macrophage cell infiltration, while the expression of FADS2 was positively correlated with the abundance of B cells. Meanwhile, SCD or FADS2 had a higher expression in monocytes/macrophages analyzed the BRCA_GSE143423 and BRCA_GSE114727_inDrop datasets. Mechanistically, the Search Tool for the Retrieval of Distant Genes and CancerSEA databases showed that SCD and FADS2 were upregulated in several cell biology signaling pathways, particularly in inflammation, apoptosis, and DNA repair. Finally, SCD or FADS2 knockdown inhibited the proliferation of MCF-7 and MDA-MB-231 cells. In summary, SCD and FADS2 play significant roles in BRCA development, suggesting that they may serve as potential therapeutic targets for BRCA treatment.

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Remdesivir inhibits the progression of glioblastoma by enhancing endoplasmic reticulum stress

Cited by 5 publications

References 50 publications

Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels

Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels

Exploring the association between inflammatory biomarkers and gastric cancer development: A two-sample mendelian randomization analysis.

Systematic analysis of fatty acid desaturases in breast invasive carcinoma: The prognosis, gene mutation, and tumor immune microenvironment

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