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

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Kasem Nithipatikom1, Daniel M Brody, Alan T Tang

  • 1Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. kasemn@mcw.edu

Cancer Science
|September 1, 2010
PubMed

Insights

Epoxyeicosatrienoic acids (EETs) drive prostate cancer cell invasion and migration. EET antagonists effectively inhibit these processes, suggesting their potential as therapeutic agents for prostate cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cytochrome P450 (CYP) epoxygenases, specifically CYP2C8, 2C9, and 2J2, are expressed in prostate cancer cells (PC-3, DU-145, LNCaP).
  • 11,12-Epoxyeicosatrienoic acid (11,12-EET) is identified as the primary arachidonic acid metabolite in these cancer cells.

Purpose of the Study:

  • To investigate the role of EETs in prostate cancer cell motility and invasion.
  • To evaluate the potential of EET antagonists as therapeutic agents for prostate cancer.

Main Methods:

  • Utilized CYP epoxygenase inhibitors (MS-PPOH) and EET antagonists (14,15-EEZE, 14,15-EEZE-PEG, 14,15-EEZE-mSI) to block EET synthesis and action.
  • Employed epidermal growth factor receptor (EGFR) and PI3 kinase inhibitors (AG494, LY294002) to explore signaling pathways.
  • Assessed cell invasion, migration, cell stretching, and microfilament formation.

Main Results:

  • Inhibition of EET synthesis reduced basal prostate cancer cell invasion and migration.
  • Exogenous EET significantly increased cell motility in a dose-dependent manner.
  • EET antagonists effectively inhibited EET-induced cell invasion and migration.
  • EETs promoted cell stretching and EGFR/Akt phosphorylation, effects reversed by EET antagonists.

Conclusions:

  • EETs promote prostate cancer cell motility and invasion, potentially through EGFR and PI3K/Akt pathways.
  • EET antagonists demonstrate significant potential in inhibiting prostate cancer cell motility.
  • EET antagonists represent promising therapeutic candidates for prostate cancer treatment.

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