Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers

Abstract

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.

Fluorescein Derivatives as Antibacterial Agents Acting via Membrane Depolarization

“…The main arguments in favor of Mitchell's chemiosmotic theory were based on the ability of uncouplers to cause the collapse of the membrane potential by carrying protons across membranes. At present, there is a revival of interest in uncouplers because of the growing evidence of their broad-spectrum therapeutic efficacy [1][2][3][4][5][6][7][8][9], including antibacterial potency [10][11][12][13][14][15][16][17][18][19], which was actually found very early [20]. To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23].…”

Identification of hub genes in cervical cancer using weighted gene co-expression network analysis

“…Next, to investigate the biological functions of hub genes, GSVA was performed. Both P53 and hypoxia pathways have important roles in tumor survival and recurrence [31][32][33]. The above results showed that these four core genes were mostly related to the P53 and hypoxia signaling pathways.…”

Mapping the lipid metabolites in follicular fluid from patients with infertility issues across ages

“…mitochondria.This is consistent with the view that niclosamide partially mediates cell death through arachidonic acid. Interestingly, AA has been found to increase mitochondrial permeability transition (PT) and cytochrome c release [13].…”