CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism.
CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism.
复制标题
类柠檬素天然产物cyp27a1依赖性抗黑色素瘤活性靶向线粒体代谢。
DOI：
10.1016/j.chembiol.2021.03.004
复制
发表时间：
2021-10-21
影响因子：
8.6
通讯作者：
Forrester WC
中科院分区：
文献类型：
--
作者：
Cho H;Shen Q;Zhang LH;Okumura M;Kawakami A;Ambrose J;Sigoillot F;Miller HR;Gleim S;Cobos-Correa A;Wang Y;Piechon P;Roma G;Eggimann F;Moore C;Aspesi P Jr;Mapa FA;Burks H;Ross NT;Krastel P;Hild M;Maimone TJ;Fisher DE;Nomura DK;Tallarico JA;Canham SM;Jenkins JL;Forrester WC
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 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.
登录
查看更多内容
影响因子：
4.3
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Steingrimsson, Eirikur
通讯作者：
Steingrimsson, Eirikur
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Corcoran RB;Dias-Santagata D;Bergethon K;Iafrate AJ;Settleman J;Engelman JA
通讯作者：
Engelman JA
影响因子：
3.7
作者：
Carson C;Raman P;Tullai J;Xu L;Henault M;Thomas E;Yeola S;Lao J;McPate M;Verkuyl JM;Marsh G;Sarber J;Amaral A;Bailey S;Lubicka D;Pham H;Miranda N;Ding J;Tang HM;Ju H;Tranter P;Ji N;Krastel P;Jain RK;Schumacher AM;Loureiro JJ;George E;Berellini G;Ross NT;Bushell SM;Erdemli G;Solomon JM
通讯作者：
Solomon JM