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NOX4 将胰腺癌中的代谢调控与内质网氧化还原易损性及其对 PRDX4 的依赖性联系起来。

NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4.

机构信息

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

出版信息

Sci Adv. 2021 May 7;7(19). doi: 10.1126/sciadv.abf7114. Print 2021 May.

DOI:10.1126/sciadv.abf7114
PMID:33962950
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8104867/
Abstract

There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces HO metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs-governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.

摘要

迫切需要识别胰腺导管腺癌 (PDAC) 的脆弱性。PDAC 细胞获得了代谢变化，增强了 NADPH 的产生和细胞溶质的氧化还原稳态。在这里，我们表明，高 NADPH 水平驱动在内质网 (ER) 膜中表达的 NADPH 氧化酶 4 (NOX4) 的活性。NOX4 在 ER 腔中产生由过氧化物酶 4 (PRDX4) 代谢的 HO。使用功能基因组学以及随后的体外和体内验证，我们发现 NADPH 水平较高的 PDAC 细胞系依赖 PRDX4 来生长和存活。PRDX4 成瘾与活性氧增加、DNA-PKcs 控制的 DNA 损伤反应和放射敏感性有关，可通过耗尽 NOX4 或 NADPH 来挽救。因此，这项研究确定了 NOX4 作为一种蛋白质，它将细胞溶质的还原力转化为 PDAC 中 ER 特异性的氧化应激脆弱性，这可能通过靶向 PRDX4 来进行治疗利用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/6b7c9898b5c6/abf7114-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/5d21d60fdcaa/abf7114-F1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/090ba9de4aee/abf7114-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/baa581f40a31/abf7114-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/6b7c9898b5c6/abf7114-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/5d21d60fdcaa/abf7114-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/3990d7cc2995/abf7114-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/090ba9de4aee/abf7114-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/baa581f40a31/abf7114-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1baa/8104867/6b7c9898b5c6/abf7114-F5.jpg

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