Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
| Autor: | C. Y. Lim, T. H. Huynh, Omer An, Y. K. Lim, P. Y. Hor, Anandhkumar Raju, Boon Cher Goh, Soo Yong Tan, Obed Akwasi Aning, Vinay Tergaonkar, Hui Ying Yang, Meiyappan Lakshmanan, Ying Swan Ho, Soo Hong Chew, Ramesh Kumar, Shuai Chen, Chit Fang Cheok, S. Y. Mak, L. Coronel, A. P. C. Wong, B. Somalanka, Hideki Itoh |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Science Mutant General Physics and Astronomy Apoptosis Arachidonate 12-Lipoxygenase General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound Mice Metabolome medicine Animals Humans Cytotoxicity lcsh:Science Gene Niclosamide Multidisciplinary Arachidonate 5-Lipoxygenase Arachidonic Acid Lipid metabolism General Chemistry HCT116 Cells Lipid Metabolism Xenograft Model Antitumor Assays Coculture Techniques Cell biology Mitochondria 030104 developmental biology chemistry Proton Ionophores Arachidonic acid lcsh:Q Calcium Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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