ARF4-mediated retrograde trafficking as a driver of chemoresistance in glioblastoma.

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY
Shreya Budhiraja, Graysen McManus, Shivani Baisiwala, Ella N Perrault, Sia Cho, Miranda Saathoff, Li Chen, Cheol H Park, Hasaan A Kazi, Crismita Dmello, Peiyu Lin, C David James, Adam M Sonabend, Dieter H Heiland, Atique U Ahmed
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引用次数: 0

Abstract

Background: Cellular 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.

Methods: To 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.

Results: Suppressing 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.

Conclusions: Our 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.

ARF4介导的逆向贩运是GBM化疗耐药性的驱动因素。
背景:细胞功能取决于蛋白质运输在空间和时间上的精心安排。逆行运输是这一过程的核心,负责将蛋白质定向到细胞核。尽管逆行运输与许多疾病有关,但它对胶质母细胞瘤(GBM)的影响仍不清楚:为了确定TMZ耐药性的遗传驱动因素,我们进行了全面的CRISPR基因敲除筛选,发现逆行运输的调节因子ADP-核糖基化因子4(ARF4)是主要的驱动因素:结果:抑制ARF4能显著提高GBM患者异种移植(PDX)模型对TMZ的敏感性,从而提高存活率(p结论:我们的研究结果表明,ARF4-基因敲除能提高GBM患者对TMZ的敏感性:我们的研究结果表明,ARF4介导的逆向运输有助于TMZ耐药性的产生,从而使这一途径成为克服GBM化疗耐药性的可行策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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