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.
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Authors | Yassir Al-Zubaidi, Yongjuan Chen, Md Khalilur Rahman, Bala Umashankar, Hassan Choucair, Kirsi Bourget, Long Chung, Yanfei Qi, Paul K Witting, Robin L Anderson, Geraldine M O'Neill, Colin R Dunstan, Tristan Rawling, Michael Murray |
Journal | Biochemical pharmacology
(Biochem Pharmacol)
Vol. 192
Pg. 114726
(10 2021)
ISSN: 1873-2968 [Electronic] England |
PMID | 34389322
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 Elsevier Inc. All rights reserved. |
Chemical References |
- Fatty Acids, Omega-3
- WNT5A protein, human
- Wnt-5a Protein
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Topics |
- Animals
- Cell Line, Tumor
- Cytoskeleton
(drug effects, metabolism)
- Fatty Acids, Omega-3
(chemistry, pharmacology)
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Invasiveness
(pathology)
- Signal Transduction
(drug effects, physiology)
- Wnt-5a Protein
(antagonists & inhibitors, metabolism)
- Xenograft Model Antitumor Assays
(methods)
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