Inhibition of carcinoma cell motility by epoxyeicosatrienoic acid (EET) antagonists

Kasem Nithipatikom, Daniel M. Brody, Alan T. Tang, Vijaya L. Manthati, J R Falck, Carol L. Williams, William B. Campbell

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Cytochrome P450 (CYP) epoxygenases, CYP2C8, 2C9 and 2J2 mRNA and proteins, were expressed in prostate carcinoma (PC-3, DU-145 and LNCaP) cells. 11,12-Epoxyeicosatrienoic acid (11,12-EET) was the major arachidonic acid metabolite in these cells. Blocking EET synthesis by a selective CYP epoxygenase inhibitor (N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide [MS-PPOH]) inhibited tonic (basal) invasion and migration (motility) while exogenously added EET induced cell motility in a concentration-dependent manner. An epidermal growth factor receptor (EGFR) kinase inhibitor (AG494) or a PI3 kinase inhibitor (LY294002) inhibited cell migration and reduced 11,12-EET-induced cell migration. Importantly, synthetic EET antagonists (14,15-epoxyeicosa-5(Z)-enoic acid [14,15-EEZE], 14,15-epoxyeicosa-5(Z)-enoic acid 2-[2-(3-hydroxy-propoxy)-ethoxy]-ethyl ester [14,15-EEZE-PEG] and 14,15-epoxyeicosa-5(Z)-enoic-methylsulfonylimide [14,15-EEZE-mSI]) inhibited EET-induced cell invasion and migration. 11,12-EET induced cell stretching and myosin-actin microfilament formation as well as increased phosphorylation of EGFR and Akt (Ser473), while 14,15-EEZE inhibited these effects. These results suggest that EET induce and EET antagonists inhibit cell motility, possibly by putative EET receptor-mediated EGFR and PI3K/Akt pathways, and suggest that EET antagonists are potential therapeutic agents for prostate cancer. (Cancer Sci 2010; 101: 2629-2636)

Original languageEnglish (US)
Pages (from-to)2629-2636
Number of pages8
JournalCancer Science
Volume101
Issue number12
DOIs
StatePublished - Dec 1 2010

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nithipatikom, K., Brody, D. M., Tang, A. T., Manthati, V. L., Falck, J. R., Williams, C. L., & Campbell, W. B. (2010). Inhibition of carcinoma cell motility by epoxyeicosatrienoic acid (EET) antagonists. Cancer Science, 101(12), 2629-2636. https://doi.org/10.1111/j.1349-7006.2010.01713.x