Faculty Collaboration Database

Inhibition of carcinoma cell motility by epoxyeicosatrienoic acid (EET) antagonists. Cancer Sci 2010 Dec;101(12):2629-36

Date

09/02/2010

Pubmed ID

20804500

Pubmed Central ID

PMC3398840

DOI

10.1111/j.1349-7006.2010.01713.x

Scopus ID

2-s2.0-78449289923 (requires institutional sign-in at Scopus site)   40 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.

Author List

Nithipatikom K, Brody DM, Tang AT, Manthati VL, Falck JR, Williams CL, Campbell WB

Authors

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Blotting, Western
Carcinoma
Cell Line, Tumor
Cell Movement
Cytochrome P-450 Enzyme System
Fluorescent Antibody Technique
Humans
Male
Prostatic Neoplasms
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction