Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers.
Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers.
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DOI：
10.1038/s41467-018-05805-1
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发表时间：
2018-09-26
影响因子：
16.6
通讯作者：
Cheok CF
中科院分区：
文献类型：
--
作者：
Kumar R;Coronel L;Somalanka B;Raju A;Aning OA;An O;Ho YS;Chen S;Mak SY;Hor PY;Yang H;Lakshmanan M;Itoh H;Tan SY;Lim YK;Wong APC;Chew SH;Huynh TH;Goh BC;Lim CY;Tergaonkar V;Cheok CF
鉴于临床中p53突变的巨大异质性，直接靶向突变型p53蛋白存在相当大的挑战。另一种方法是利用野生型p53缺失所引起的细胞适应性改变。在这里，我们确定氯硝柳胺通过HTS筛选化合物选择性杀死p53缺陷细胞。氯硝柳胺损害p53缺陷细胞和p53突变患者来源的卵巢异种移植物的生长。代谢物组分析表明，氯硝柳胺诱导线粒体解偶联，这使得突变型p53细胞容易通过花生四烯酸（AA）的优先积累的神经依赖性凋亡，并代表了第一类抑制剂的p53突变型肿瘤。野生型p53通过促进两个关键的脂质氧化基因ALOX 5和ALOX 12 B的转录诱导来逃避细胞毒性，所述基因催化AA的二氧化和分解。因此，我们提出了一种新的模式，针对癌症缺陷的p53通路，利用他们的脆弱性氯硝柳胺诱导的线粒体解偶联。直接靶向突变型p53涉及几个挑战，而靶向野生型p53缺失的细胞适应性改变是一种替代方法。在这里，他们确定氯硝柳胺通过以前未知的线粒体解偶联机制对p53缺陷细胞具有选择性毒性。
There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling. Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.
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影响因子：
64.5
作者：
Dessen, A;Tang, J;Somers, WS
通讯作者：
Somers, WS
影响因子：
--
作者：
Arend RC;Londoño-Joshi AI;Gangrade A;Katre AA;Kurpad C;Li Y;Samant RS;Li PK;Landen CN;Yang ES;Hidalgo B;Alvarez RD;Straughn JM;Forero A;Buchsbaum DJ
通讯作者：
Buchsbaum DJ
影响因子：
5.5
作者：
Li, Z;Lee, HC;Abboud, FM
通讯作者：
Abboud, FM
影响因子：
11.2
作者：
Jin, Yanli;Lu, Zhongzheng;Pan, Jingxuan
通讯作者：
Pan, Jingxuan
DOI：
10.1073/pnas.89.13.6147
发表时间：
1992-07-01
影响因子：
11.1
作者：
LIN, LL;LIN, AY;KNOPF, JL
通讯作者：
KNOPF, JL