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

R. Kumar, L. Coronel, B. Somalanka, A. Raju, O. A. Aning, O. An, Y. S. Ho, Song Chen, S. Y. Mak, P. Y. Hor, H. Yang, M. Lakshmanan, H. Itoh, S. Y. Tan, Y. K. Lim, A. P. C. Wong, S. H. Chew, T. H. Huynh, B. C. Goh, C. Y. Lim, V. Tergaonkar and C. F. Cheok ()
Additional contact information
R. Kumar: IFOM
L. Coronel: IFOM
B. Somalanka: p53 Laboratory, Agency for Science Technology and Research
A. Raju: Agency for Science Technology and Research
O. A. Aning: Agency for Science Technology and Research
O. An: National University of Singapore
Y. S. Ho: Agency for Science Technology and Research
S. Y. Mak: Agency for Science Technology and Research
P. Y. Hor: p53 Laboratory, Agency for Science Technology and Research
H. Yang: National University of Singapore
M. Lakshmanan: Agency for Science Technology and Research
H. Itoh: Agency for Science Technology and Research
S. Y. Tan: Agency for Science Technology and Research
Y. K. Lim: KK Women’s and Children’s Hospital
A. P. C. Wong: KK Women’s and Children’s Hospital
S. H. Chew: KK Women’s and Children’s Hospital
T. H. Huynh: National Cancer Centre Singapore
B. C. Goh: National University of Singapore
C. Y. Lim: Agency for Science Technology and Research
V. Tergaonkar: Agency for Science Technology and Research
C. F. Cheok: IFOM

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-05805-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05805-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-05805-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().