CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism. Issue 10 (21st October 2021)

• Record Type: Journal Article
• Authors: Cho, Hyelim; Shen, Qiong; Zhang, Lydia H.; Okumura, Mikiko; Kawakami, Akinori; Ambrose, Jessi; Sigoillot, Frederic; Miller, Howard R.; Gleim, Scott; Cobos-Correa, Amanda; Wang, Ying; Piechon, Philippe; Roma, Guglielmo; Eggimann, Fabian; Moore, Charles; Aspesi, Peter; Mapa, Felipa A.; Burks, Heather; Ross, Nathan T.; Krastel, Philipp; Hild, Marc; Maimone, Thomas J.; Fisher, David E.; Nomura, Daniel K.; Tallarico, John A.; Canham, Stephen M.; Jenkins, Jeremy L.; Forrester, William C.
• Is Part Of: Cell chemical biology. Volume 28:Issue 10(2021)
• Page Start: 1407
• Page End: 1419.e6
• Publication Date: 2021-10-21
• Subjects: natural products -- MITF -- CYP27A1 -- prodrug -- melanoma -- oncology -- BRAF -- cancer metabolism -- oxidative phosphorylation -- mitochondrial complex I; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.03.004
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: The limonoid, harrpernoid D, was isolated and described Harrperonid D is activated by CYP27A1, to overcome BRAFi-resistant melanoma Metabolism of harrpernoid D into a reactive enedial modifies mitochondrial proteins Abstract : Selective targeting of melanoma cells by limonoid natural products involves their conversion to a reactive electrophilic metabolite by CYP27A1, a mitochondrial cytochrome p450 enzyme, leading to toxic adducts of key mitochondrial proteins. CYP27A1 is a target gene of MITF, the oncogenic transcription factor deregulated in melanoma.