Canham, Steve, Jenkins, Jeremy, Forrester, William, Hild, Marc, Ambrose, Jessi, Sigoillot, Frederic, Gleim, Scott, Cobos-Correa, Amanda, Wang, Ying, Eggimann, Fabian, Moore, Charles, Mapa, Felipa, Burks, Heather, Roma, Guglielmo, Krastel, Philipp, Tallarico, John, Nomura, Daniel, Fisher, David, Zhang, Lydia, Cho, Hyelim, Shen, Qiong, Okumura, Mikiko, Kawakami, Akinori, Miller, Howard, Dix, Ina and Ross, Nathan (2021) CYP27A1 dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism. Cell chemical biology. ISSN 24519456

Abstract

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 MITF. We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide siRNA screen in combination with chemical proteomics experiments revealed genedrug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics. 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.

Item Type:	Article
Keywords:	Natural products, MITF, CYP27A1, pro-drug, melanoma, oncology, BRAF, cancer metabolism, oxidative phosphorylation, mitochondrial complex I
Date Deposited:	25 May 2021 00:45
Last Modified:	25 May 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43674