Inhibition of carcinoma cell motility by epoxyeicosatrienoic acid (EET) antagonists.
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.
Nithipatikom
Kasem
K
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. kasemn@mcw.edu
Brody
Daniel M
DM
Tang
Alan T
AT
Manthati
Vijaya L
VL
Falck
John R
JR
Williams
Carol L
CL
Campbell
William B
WB
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C494022:14,15-eicosa-5-enoic acid; D012333:RNA, Messenger; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid
J Biol Chem. 2008 Jan 11;283(2):963-76
17951244
Hypertension. 2003 Oct;42(4):555-61
12953017
Br J Cancer. 2006 Jul 17;95(2):164-71
16804520
J Pharmacol Exp Ther. 2008 Mar;324(3):1019-27
18171909
Circ Res. 2002 May 17;90(9):1028-36
12016270
J Biol Chem. 2006 Jan 13;281(2):905-14
16286479
J Pharmacol Exp Ther. 2007 Jun;321(3):1023-31
17327488
Cancer Res. 2007 Jul 15;67(14):6665-74
17638876
J Mol Histol. 2006 May;37(3-4):133-41
16957870
Prostate. 2003 Jun 15;56(1):1-12
12746841
Acta Pharmacol Sin. 2010 Feb;31(2):211-8
20139904
Prostate. 2003 Jun 1;55(4):281-91
12712407
Arch Biochem Biophys. 1995 Jul 10;320(2):380-9
7625847
Cancer Res. 2004 Dec 15;64(24):8826-30
15604240
Cell Signal. 2005 Nov;17(11):1449-55
16125057
Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1242-7
18326754
Drug Metab Pharmacokinet. 2005 Dec;20(6):478-84
16415532
Virchows Arch. 1999 May;434(5):401-11
10389623
Yakugaku Zasshi. 2003 May;123(5):369-75
12772594
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6029-34
11983897
J Mol Med (Berl). 2005 Dec;83(12):1014-24
16211407
J Pharmacol Exp Ther. 2005 Aug;314(2):522-32
15840765
Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H724-35
18055514
Int J Cancer. 2007 Sep 1;121(5):984-91
17443494
Anal Biochem. 2001 Nov 15;298(2):327-36
11700990
Biochem Biophys Res Commun. 2005 Feb 25;327(4):1052-7
15652503
J Cell Sci. 2005 Dec 1;118(Pt 23):5489-98
16291720
Cancer Lett. 2004 Nov 8;215(1):69-78
15374634
Cancer Res. 2005 Jun 1;65(11):4707-15
15930289
Drug Metab Dispos. 2004 Aug;32(8):840-7
15258110
APMIS. 2006 Jan;114(1):61-6
16499663
Curr Opin Cell Biol. 1999 Apr;11(2):197-202
10209147