Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-018-05805-1
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dc.titleMitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
dc.contributor.authorKumar, R
dc.contributor.authorCoronel, L
dc.contributor.authorSomalanka, B
dc.contributor.authorRaju, A
dc.contributor.authorAning, OA
dc.contributor.authorAn, O
dc.contributor.authorHo, YS
dc.contributor.authorChen, S
dc.contributor.authorMak, SY
dc.contributor.authorHor, PY
dc.contributor.authorYang, H
dc.contributor.authorLakshmanan, M
dc.contributor.authorItoh, H
dc.contributor.authorTan, SY
dc.contributor.authorLim, YK
dc.contributor.authorWong, APC
dc.contributor.authorChew, SH
dc.contributor.authorHuynh, TH
dc.contributor.authorGoh, BC
dc.contributor.authorLim, CY
dc.contributor.authorTergaonkar, V
dc.contributor.authorCheok, CF
dc.date.accessioned2019-06-06T01:28:10Z
dc.date.available2019-06-06T01:28:10Z
dc.date.issued2018-09-26
dc.identifier.citationKumar, 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 (2018-09-26). Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. NATURE COMMUNICATIONS 9 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-018-05805-1
dc.identifier.issn2041-1723
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/155186
dc.description.abstract© 2018, The Author(s). 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.
dc.language.isoen
dc.publisherNATURE PUBLISHING GROUP
dc.sourceElements
dc.subjectScience & Technology
dc.subjectMultidisciplinary Sciences
dc.subjectScience & Technology - Other Topics
dc.subjectCYTOCHROME-C
dc.subjectSTEM-CELLS
dc.subjectNICLOSAMIDE
dc.subjectP53
dc.subjectPROTEIN
dc.subjectTARGET
dc.subjectDEATH
dc.subjectACTIVATION
dc.subjectMECHANISMS
dc.subjectINHIBITION
dc.typeArticle
dc.date.updated2019-06-03T08:03:19Z
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentBIOCHEMISTRY
dc.contributor.departmentPATHOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1038/s41467-018-05805-1
dc.description.sourcetitleNATURE COMMUNICATIONS
dc.description.volume9
dc.description.issue1
dc.published.statePublished
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