CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism
| Autor: | Qiong Shen, William C. Forrester, Philipp Krastel, David E. Fisher, Jessi Ambrose, Daniel K. Nomura, Jeremy L. Jenkins, Nathan T. Ross, Lydia H. Zhang, Marc Hild, Akinori Kawakami, Hyelim Cho, Amanda Cobos-Correa, Fabian K. Eggimann, Howard R Miller, Scott Gleim, Frederic Sigoillot, John A. Tallarico, Charles Moore, Philippe Piechon, Ying Wang, Mikiko Okumura, Peter Aspesi, Felipa A. Mapa, Burks Heather Elizabeth, Thomas J. Maimone, Stephen M. Canham, Guglielmo Roma |
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| Rok vydání: | 2021 |
| Předmět: |
Limonins
Proto-Oncogene Proteins B-raf Neuroblastoma RAS viral oncogene homolog Small interfering RNA Clinical Biochemistry Mutant Antineoplastic Agents Oxidative phosphorylation Biology 01 natural sciences Biochemistry Oxidative Phosphorylation Transcriptome Cell Line Tumor Drug Discovery Humans RNA Small Interfering Promoter Regions Genetic Melanoma Molecular Biology Transcription factor Cell Proliferation Pharmacology Biological Products Microphthalmia-Associated Transcription Factor 010405 organic chemistry Microphthalmia-associated transcription factor Mitochondria 0104 chemical sciences Cell biology Mitochondrial biogenesis Cholestanetriol 26-Monooxygenase Molecular Medicine RNA Interference Protein Binding |
| Zdroj: | Cell Chemical Biology. 28:1407-1419.e6 |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2021.03.004 |
| Popis: | Three limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation-dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of melanogenesis-associated transcription factor (MITF). We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide small interfering RNA screen in combination with chemical proteomics experiments revealed gene-drug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics through a covalent mechanism. Our work suggests a strategy for melanoma-specific targeting by exploiting the expression of MITF target gene CYP27A1 and inhibiting mitochondrial oxidative phosphorylation in BRAF mutant melanomas. |
| Databáze: | OpenAIRE |
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