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2-氨基乙硫醇双加氧酶催化的牛磺酸合成作为胰腺癌中一种易损的代谢改变

Taurine Synthesis by 2-Aminoethanethiol Dioxygenase as a Vulnerable Metabolic Alteration in Pancreatic Cancer.

作者信息

Nam Hoonsik, Lee Woohyung, Lee Yun Ji, Kim Jin-Mo, Jung Kyung Hee, Hong Soon-Sun, Kim Song Cheol, Park Sunghyouk

机构信息

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea.

出版信息

Biomol Ther (Seoul). 2025 Jan 1;33(1):143-154. doi: 10.4062/biomolther.2024.086. Epub 2024 Dec 5.

DOI:10.4062/biomolther.2024.086
PMID:39637922
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11704412/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits an altered metabolic profile compared to normal pancreatic tissue. However, studies on actual pancreatic tissues are limited. Untargeted metabolomics analysis was conducted on 54 pairs of tumor and matched normal tissues. Taurine levels were validated via immunohistochemistry (IHC) on separate PDAC and normal tissues. Bioinformatics analysis of transcriptomics and proteomics data evaluated genes associated with taurine metabolism. Identified taurine-associated gene was validated through gene modulation. Clinical implications were evaluated using patient data. Metabolomics analysis showed a 2.51-fold increase in taurine in PDAC compared to normal tissues (n=54). IHC confirmed this in independent samples (n=99 PDAC, 19 normal). Bioinformatics identified 2-aminoethanethiol dioxygenase (ADO) as a key gene modulating taurine metabolism. IHC on a tissue microarray (39 PDAC, 10 normal) confirmed elevated ADO in PDAC. The ADO-Taurine axis correlated with PDAC recurrence and disease-free survival. ADO knockdown reduced cancer cell proliferation and tumor growth in a mouse xenograft model. The MEK-related signaling pathway is suggested to be modulated by ADO-Taurine metabolism. Our multi-omics investigation revealed elevated taurine synthesis mediated by ADO upregulation in PDAC. The ADO-Taurine axis may serve as a biomarker for PDAC prognosis and a therapeutic target.

摘要

与正常胰腺组织相比，胰腺导管腺癌（PDAC）呈现出代谢谱的改变。然而，对实际胰腺组织的研究有限。对54对肿瘤组织和配对的正常组织进行了非靶向代谢组学分析。通过对单独的PDAC组织和正常组织进行免疫组织化学（IHC）验证了牛磺酸水平。对转录组学和蛋白质组学数据进行生物信息学分析，评估与牛磺酸代谢相关的基因。通过基因调控验证了鉴定出的与牛磺酸相关的基因。使用患者数据评估临床意义。代谢组学分析显示，与正常组织相比，PDAC中的牛磺酸增加了2.51倍（n = 54）。IHC在独立样本中证实了这一点（n = 99例PDAC，19例正常）。生物信息学确定2-氨基乙硫醇双加氧酶（ADO）是调节牛磺酸代谢的关键基因。对组织芯片（39例PDAC，10例正常）进行的IHC证实PDAC中ADO升高。ADO-牛磺酸轴与PDAC复发和无病生存期相关。在小鼠异种移植模型中，敲低ADO可降低癌细胞增殖和肿瘤生长。提示MEK相关信号通路受ADO-牛磺酸代谢调节。我们的多组学研究表明，PDAC中ADO上调介导牛磺酸合成增加。ADO-牛磺酸轴可能作为PDAC预后的生物标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/cd242c7a8c62/bt-33-1-143-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/7747e606b5be/bt-33-1-143-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/bfee419ffc14/bt-33-1-143-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/a955382ab39e/bt-33-1-143-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/a04282b808b1/bt-33-1-143-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/0e6d01df452e/bt-33-1-143-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/cd242c7a8c62/bt-33-1-143-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/7747e606b5be/bt-33-1-143-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/bfee419ffc14/bt-33-1-143-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/a955382ab39e/bt-33-1-143-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/a04282b808b1/bt-33-1-143-f4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a357/11704412/cd242c7a8c62/bt-33-1-143-f6.jpg

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The role of taurine in male reproduction: Physiology, pathology and toxicology.牛磺酸在男性生殖中的作用：生理学、病理学和毒理学。
Front Endocrinol (Lausanne). 2023 Jan 18;14:1017886. doi: 10.3389/fendo.2023.1017886. eCollection 2023.
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Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.线粒体 GPD2 的非生物能量作用促进肿瘤进展。
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Taurine and Its Anticancer Functions: In Vivo and In Vitro Study.牛磺酸及其抗癌功能：体内和体外研究。
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