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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.bcp.2021.114726
Journal or Publication Title: Biochemical Pharmacology
Volume: 192
Page Range: p. 114726
Date: October 2021
Divisions: Lipid Cell Biology
Depositing User: General Admin
Identification Number: 10.1016/j.bcp.2021.114726
ISSN: 00062952
Date Deposited: 06 Oct 2021 05:16
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.

Keywords: Actin cytoskeleton; Cancer cell migration; Wnt5a; ω-3 fatty acid epoxide isosteres.

Copyright © 2021 Elsevier Inc. All rights reserved.

Creators:
Creators
Email
al-Zubaidi, Yassir
UNSPECIFIED
Chen, Yongjuan
UNSPECIFIED
Khalilur Rahman, Md.
UNSPECIFIED
Umashankar, Bala
UNSPECIFIED
Choucair, Hassan
UNSPECIFIED
Bourget, Kirsi
UNSPECIFIED
Chung, Long
UNSPECIFIED
Qi, Yanfei
UNSPECIFIED
Witting, Paul K.
UNSPECIFIED
Anderson, Robin L.
UNSPECIFIED
O'Neill, Geraldine M.
UNSPECIFIED
Dunstan, Colin R.
UNSPECIFIED
Rawling, Tristan
UNSPECIFIED
Murray, Michael
UNSPECIFIED
Last Modified: 06 Oct 2021 05:16
URI: https://eprints.centenary.org.au/id/eprint/1140

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