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

IF 4.5 2区医学 Q1 ONCOLOGY

Cancer Science Pub Date : 2024-07-15 DOI:10.1111/cas.16289

Yukiko Kojima, Saki Fujieda, Liya Zhou, Masahiro Takikawa, Kouji Kuramochi, Toshiki Furuya, Ayaka Mizumoto, Noritaka Kagaya, Teppei Kawahara, Kazuo Shin-ya, Shingo Dan, Akihiro Tomida, Fuyuki Ishikawa, Mahito Sadaie

{"title":"Cytochrome P450 2J2 is required for the natural compound austocystin D to elicit cancer cell toxicity","authors":"Yukiko Kojima, Saki Fujieda, Liya Zhou, Masahiro Takikawa, Kouji Kuramochi, Toshiki Furuya, Ayaka Mizumoto, Noritaka Kagaya, Teppei Kawahara, Kazuo Shin-ya, Shingo Dan, Akihiro Tomida, Fuyuki Ishikawa, Mahito Sadaie","doi":"10.1111/cas.16289","DOIUrl":null,"url":null,"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.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 9","pages":"3054-3066"},"PeriodicalIF":4.5000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16289","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Science","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cas.16289","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

细胞色素 P450 2J2 是天然化合物奥斯特胱氨酸 D 引发癌细胞毒性的必要条件。

奥斯特胱氨酸 D 是一种天然化合物，可诱导细胞色素 P450（CYP）单氧酶依赖性 DNA 损伤，并抑制某些癌细胞系的生长。对奥司他胱 D 敏感性较高的癌细胞通常会显示 CYP2J2 表达升高。然而，CYP2J2 在这种化合物的细胞毒性中的重要性和作用仍不清楚。在这项研究中，我们证明了 CYP2J2 的缺失会减轻奥司他胱 D 的敏感性和 DNA 损伤诱导，而 CYP2J2 的过表达则会增强它们。此外，对参与奥司他胱锡 D 细胞毒性的基因的研究还发现了 CYP 活性的正调控因子 POR 和 PGRMC1，以及组蛋白乙酰转移酶 KAT7。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。这些发现有力地表明，CYP2J2 对奥斯特胱氨酸 D 的代谢及其随后的细胞毒性作用至关重要。我们强调了奥斯特胱氨酸 D 作为治疗原药的潜在用途，特别是在癌症中，CYP2J2 表达的升高可作为一种生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer Science 医学-肿瘤学

自引率

3.50%

发文量

406

审稿时长

2 months

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.