R. Kumar 1 , 2 , L. Coronel 1 , 3 , B. Somalanka 3 , A. Raju 4 , O. A. Aning 4 , O. An 5 , Y. S. Ho 6 , S. Chen 6 , S. Y. Mak 6 , P. Y. Hor 3 , H. Yang 5 , M. Lakshmanan 4 , 7 , H. Itoh 8 , S. Y. Tan 4 , 7 , Y. K. Lim 9 , A. P. C. Wong 10 , S. H. Chew 10 , T. H. Huynh 11 , 12 , B. C. Goh 5 , 12 , 13 , C. Y. Lim 8 , 14 , V. Tergaonkar 4 , 14 , C. F. Cheok , 1 , 4 , 7 , 14
26 September 2018
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.