PTU, a novel ureido-fatty acid, inhibits MDA-MB-231 cell invasion and dissemination by modulating Wnt5a secretion and cytoskeletal signaling.

Al-Zubaidi, Y; Chen, Y; Khalilur Rahman, M; Umashankar, B; Choucair, H; Bourget, K; Chung, L; Qi, Y; Witting, PK; Anderson, RL; O'Neill, GM; Dunstan, CR; Rawling, T; Murray, M

PTU, a novel ureido-fatty acid, inhibits MDA-MB-231 cell invasion and dissemination by modulating Wnt5a secretion and cytoskeletal signaling.

Al-Zubaidi, Y Chen, Y Khalilur Rahman, M Umashankar, B Choucair, H Bourget, K Chung, L Qi, Y Witting, PK Anderson, RL O'Neill, GM Dunstan, CR Rawling, T

Murray, M

Permalink

Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Biochemical Pharmacology, 2021, 192, pp. 1-12
Issue Date:: 2021-10

Closed Access

	Filename	Description	Size
	1-s2.0-S0006295221003427-main.pdf		4.65 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Al-Zubaidi, Y
dc.contributor.author	Chen, Y
dc.contributor.author	Khalilur Rahman, M
dc.contributor.author	Umashankar, B
dc.contributor.author	Choucair, H
dc.contributor.author	Bourget, K
dc.contributor.author	Chung, L
dc.contributor.author	Qi, Y
dc.contributor.author	Witting, PK
dc.contributor.author	Anderson, RL
dc.contributor.author	O'Neill, GM
dc.contributor.author	Dunstan, CR
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Murray, M
dc.date.accessioned	2022-02-14T03:15:27Z
dc.date.available	2021-08-06
dc.date.available	2022-02-14T03:15:27Z
dc.date.issued	2021-10
dc.identifier.citation	Biochemical Pharmacology, 2021, 192, pp. 1-12
dc.identifier.issn	0006-2952
dc.identifier.issn	1873-2968
dc.identifier.uri	http://hdl.handle.net/10453/154485
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Biochemical Pharmacology
dc.relation.isbasedon	10.1016/j.bcp.2021.114726
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Pharmacology & Pharmacy
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cytoskeleton
dc.subject.mesh	Fatty Acids, Omega-3
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Wnt-5a Protein
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cytoskeleton
dc.subject.mesh	Fatty Acids, Omega-3
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Wnt-5a Protein
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cytoskeleton
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Fatty Acids, Omega-3
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Female
dc.subject.mesh	Wnt-5a Protein
dc.title	PTU, a novel ureido-fatty acid, inhibits MDA-MB-231 cell invasion and dissemination by modulating Wnt5a secretion and cytoskeletal signaling.
dc.type	Journal Article
utslib.citation.volume	192
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-02-14T03:15:24Z
pubs.publication-status	Published
pubs.volume	192

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/154485