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Title: PTU, a novel ureido-fatty acid, inhibits MDA-MB-231 cell invasion and dissemination by modulating Wnt5a secretion and cytoskeletal signaling.
Austin Authors: Al-Zubaidi, Yassir;Chen, Yongjuan;Khalilur Rahman, Md;Umashankar, Bala;Choucair, Hassan;Bourget, Kirsi;Chung, Long;Qi, Yanfei;Witting, Paul K;Anderson, Robin L ;O'Neill, Geraldine M;Dunstan, Colin R;Rawling, Tristan;Murray, Michael
Affiliation: School of Cancer Medicine, La Trobe University, Bundoora, VIC 3083, Australia
School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
Olivia Newton-John Cancer Research Institute
Centenary Institute, The University of Sydney, NSW 2050, Australia
School of Biomedical Engineering, University of Sydney, NSW 2006, Australia
Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia
Discipline of Pathology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia
Children's Cancer Research Unit, the Children's Hospital at Westmead, Westmead, NSW 2145; Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia
Issue Date: Oct-2021
Date: 2021-08-10
Publication information: Biochemical Pharmacology 2021; 192: 114726
Abstract: Migration and invasion promote tumor cell metastasis, which is the leading cause of cancer death. At present there are no effective treatments. Epidemiological studies have suggested that ω-3 polyunsaturated fatty acids (PUFA) may decrease cancer aggressiveness. In recent studies epoxide metabolites of ω-3 PUFA exhibited anti-cancer activity, although increased in vivo stability is required to develop useful drugs. Here we synthesized novel stabilized ureido-fatty acid ω-3 epoxide isosteres and found that one analogue - p-tolyl-ureidopalmitic acid (PTU) - inhibited migration and invasion by MDA-MB-231 breast cancer cells in vitro and in vivo in xenografted nu/nu mice. From proteomics analysis of PTU-treated cells major regulated pathways were linked to the actin cytoskeleton and actin-based motility. The principal finding was that PTU impaired the formation of actin protrusions by decreasing the secretion of Wnt5a, which dysregulated the Wnt/planar cell polarity (PCP) pathway and actin cytoskeletal dynamics. Exogenous Wnt5a restored invasion and Wnt/PCP signalling in PTU-treated cells. PTU is the prototype of a novel class of agents that selectively dysregulate the Wnt/PCP pathway by inhibiting Wnt5a secretion and actin dynamics to impair MDA-MB-231 cell migration and invasion.
DOI: 10.1016/j.bcp.2021.114726
Journal: Biochemical Pharmacology
PubMed URL: 34389322
Type: Journal Article
Subjects: Wnt5a
actin cytoskeleton
cancer cell migration
ω-3 fatty acid epoxide isosteres
Appears in Collections:Journal articles

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