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

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

doi:10.1016/j.bcp.2021.114726

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

Biochem Pharmacol. 2021 Oct:192:114726. doi: 10.1016/j.bcp.2021.114726. Epub 2021 Aug 10.

Authors

Affiliations

¹ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia; College of Pharmacy, The University of Mashreq, Baghdad, Iraq.
² Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia.
³ Centenary Institute, The University of Sydney, NSW 2050, Australia.
⁴ Discipline of Pathology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia.
⁵ Translational Breast Cancer Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, VIC 3083, Australia.
⁶ Children's Cancer Research Unit, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia.
⁷ School of Biomedical Engineering, University of Sydney, NSW 2006, Australia.
⁸ School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
⁹ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia. Electronic address: michael.murray@sydney.edu.au.

PMID: 34389322
DOI: 10.1016/j.bcp.2021.114726

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cytoskeleton / drug effects
Cytoskeleton / metabolism*
Fatty Acids, Omega-3 / chemistry
Fatty Acids, Omega-3 / pharmacology*
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness / pathology
Signal Transduction / drug effects
Signal Transduction / physiology*
Wnt-5a Protein / antagonists & inhibitors*
Wnt-5a Protein / metabolism*
Xenograft Model Antitumor Assays / methods

Substances

Fatty Acids, Omega-3
WNT5A protein, human
Wnt-5a Protein