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

• Published in: Biochemical pharmacology Vol. 192; p. 114726
• Main 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2021
• Subjects: Actin cytoskeleton; Cancer cell migration; Wnt5a; ω-3 fatty acid epoxide isosteres; DMSO; MLC; PTU; BSA; DMEM; HRMS; Wnt5a; FBS; RT-PCR; Rho; ESI; CYP; Wnt; PBS; SDS; PUFA; DAPI; rWnt5a; EPA; LIM kinase; ω-3 fatty acid epoxide isosteres; DVL-2; Cancer cell migration; IPA; PCP; Actin cytoskeleton
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114726

[Display omitted] 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.