Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.

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Tác giả: Yueyue Chen, Mingzhu Liu, Yimei Liu, Ping Lu, Tiebo Mao, Ningning Niu, Xuqing Shen, Yingying Tang, Yujie Tang, Liwei Wang, Yawen Weng, Jing Xue, Feier Yu

Ngôn ngữ: eng

Ký hiệu phân loại: 785.13 *Trios

Thông tin xuất bản: United States : Cell reports. Medicine , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 679399

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.
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