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Multi-targeted therapy resistance via drug-induced secretome fucosylation

التفاصيل البيبلوغرافية
العنوان: Multi-targeted therapy resistance via drug-induced secretome fucosylation
المؤلفون: Mark Borris D Aldonza, Junghwa Cha, Insung Yong, Jayoung Ku, Pavel Sinitcyn, Dabin Lee, Ryeong-Eun Cho, Roben D Delos Reyes, Dongwook Kim, Soyeon Kim, Minjeong Kang, Yongsuk Ku, Geonho Park, Hye-Jin Sung, Han Suk Ryu, Sukki Cho, Tae Min Kim, Pilnam Kim, Je-Yoel Cho, Yoosik Kim
المصدر: eLife, Vol 12 (2023)
بيانات النشر: eLife Sciences Publications Ltd, 2023.
سنة النشر: 2023
المجموعة: LCC:Medicine
LCC:Science
LCC:Biology (General)
مصطلحات موضوعية: fucosylation, n-linked glycosylation, targeted therapy, secretome, drug resistance, cancer, Medicine, Science, Biology (General), QH301-705.5
الوصف: Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2050-084X
Relation: https://elifesciences.org/articles/75191; https://doaj.org/toc/2050-084X
DOI: 10.7554/eLife.75191
URL الوصول: https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f
رقم الأكسشن: edsdoj.04cffef7074f4c568c8aa2b97115d57f
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:2050084X
DOI:10.7554/eLife.75191