ArticleNeuro-oncology2024
ARF4-mediated retrograde trafficking as a driver of chemoresistance in glioblastoma.
Article in Neuro-oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 2 citations in OpenAlex.
- Protease inhibition: breaking the barriers of chemoresistance in cancer.Molecular biology reports · 2026Review
- Decoding and Overcoming Temozolomide Resistance Through CRISPR/Cas Technologies.Molecular diagnosis & therapy · 2026Review
- MAPK pathway inhibitors enhance radioiodine sensitivity in anaplastic thyroid carcinoma through promoting NIS expression and ARF4-mediated NIS membrane transport.Scientific reports · 2026Article
- Modeling blood-brain barrier-glioblastoma interactions: implications for chemoresistance and therapeutic targeting.Fluids and barriers of the CNS · 2026Review
- LMNA-PRKDC axis enhances DNA repair and promotes chemoresistance in glioblastoma.Cell death & disease · 2025Article
- Decoding ARF4 and EIF5B-Based Prognostic Signatures and Immune Landscape Following Insufficient Radiofrequency Ablation in Hepatocellular Carcinoma: Through Multi-Omics and Experimental Validation.Journal of hepatocellular carcinoma · 2025Article
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundCellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins to the nucleus. Despite its link to many diseases, the implications of retrograde trafficking in glioblastoma (GBM) are still unclear.
methodsTo identify genetic drivers of TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator of retrograde trafficking, as a major contributor.
resultsSuppressing ARF4 significantly enhanced TMZ sensitivity in GBM patient-derived xenograft (PDX) models, leading to improved survival rates (P < .01) in both primary and recurrent lines. We also observed that TMZ exposure stimulates ARF4-mediated retrograde trafficking. Proteomics analysis of GBM cells with varying levels of ARF4 unveiled the influence of this pathway on EGFR signaling, with increased nuclear trafficking of EGFR observed in cells with ARF4 overexpression and TMZ treatment. Additionally, spatially resolved RNA-sequencing of GBM patient tissues revealed substantial correlations between ARF4 and crucial nuclear EGFR (nEGFR) downstream targets, such as MYC, STAT1, and DNA-PK. Decreased activity of DNA-PK, a DNA repair protein downstream of nEGFR signaling that contributes to TMZ resistance, was observed in cells with suppressed ARF4 levels. Notably, treatment with DNA-PK inhibitor, KU-57788, in mice with a recurrent PDX line resulted in prolonged survival (P < .01), highlighting the promising therapeutic implications of targeting proteins reliant on ARF4-mediated retrograde trafficking.
conclusionsOur findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.
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