1. Cytochrome P450 2J2 is required for the natural compound austocystin D to elicit cancer cell toxicity.
- Author
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Kojima Y, Fujieda S, Zhou L, Takikawa M, Kuramochi K, Furuya T, Mizumoto A, Kagaya N, Kawahara T, Shin-Ya K, Dan S, Tomida A, Ishikawa F, and Sadaie M
- Subjects
- Humans, Cell Line, Tumor, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Neoplasms metabolism, Gene Expression Regulation, Neoplastic drug effects, Membrane Proteins genetics, Membrane Proteins metabolism, Cytochrome P-450 Enzyme System metabolism, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 CYP2J2, DNA Damage drug effects
- 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., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2024
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