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细胞色素 P450 2J2 是天然化合物 austocystin D 引起癌细胞毒性所必需的。

Cytochrome P450 2J2 is required for the natural compound austocystin D to elicit cancer cell toxicity.

机构信息

Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.

Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

出版信息

Cancer Sci. 2024 Sep;115(9):3054-3066. doi: 10.1111/cas.16289. Epub 2024 Jul 15.

DOI:10.1111/cas.16289
PMID:39009033
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11462933/
Abstract

Austocystin D is a natural compound that induces cytochrome P450 (CYP) monooxygenase-dependent DNA damage and growth inhibition in certain cancer cell lines. Cancer cells exhibiting higher sensitivity to austocystin D often display elevated CYP2J2 expression. However, the essentiality and the role of CYP2J2 for the cytotoxicity of this compound remain unclear. In this study, we demonstrate that CYP2J2 depletion alleviates austocystin D sensitivity and DNA damage induction, while CYP2J2 overexpression enhances them. Moreover, the investigation into genes involved in austocystin D cytotoxicity identified POR and PGRMC1, positive regulators for CYP activity, and KAT7, a histone acetyltransferase. Through genetic manipulation and analysis of multiomics data, we elucidated a role for KAT7 in CYP2J2 transcriptional regulation. These findings strongly suggest that CYP2J2 is crucial for austocystin D metabolism and its subsequent cytotoxic effects. The potential use of austocystin D as a therapeutic prodrug is underscored, particularly in cancers where elevated CYP2J2 expression serves as a biomarker.

摘要

奥斯特辛 D 是一种天然化合物，可诱导某些癌细胞系中的细胞色素 P450（CYP）单加氧酶依赖性 DNA 损伤和生长抑制。对奥斯特辛 D 表现出更高敏感性的癌细胞通常显示 CYP2J2 表达升高。然而，CYP2J2 对于该化合物的细胞毒性的必要性和作用仍不清楚。在这项研究中，我们证明 CYP2J2 耗竭可减轻奥斯特辛 D 的敏感性和 DNA 损伤诱导，而 CYP2J2 过表达则增强了它们。此外，对涉及奥斯特辛 D 细胞毒性的基因的研究确定了 POR 和 PGRMC1，它们是 CYP 活性的正调节剂，以及 KAT7，一种组蛋白乙酰转移酶。通过遗传操作和多组学数据分析，我们阐明了 KAT7 在 CYP2J2 转录调控中的作用。这些发现强烈表明 CYP2J2 对于奥斯特辛 D 的代谢及其随后的细胞毒性作用至关重要。奥斯特辛 D 作为治疗前药的潜在用途得到了强调，特别是在 CYP2J2 表达升高作为生物标志物的癌症中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/bf4e1ce938bc/CAS-115-3054-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/9dae4ee7eed1/CAS-115-3054-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/8108dcf98d3c/CAS-115-3054-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/dbd36a30f2b2/CAS-115-3054-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/10446741339a/CAS-115-3054-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/bf4e1ce938bc/CAS-115-3054-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/9dae4ee7eed1/CAS-115-3054-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/8108dcf98d3c/CAS-115-3054-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/dbd36a30f2b2/CAS-115-3054-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/10446741339a/CAS-115-3054-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9939/11462933/bf4e1ce938bc/CAS-115-3054-g002.jpg

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