title: Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria.
abstract: Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential and apoptosis in human cervical carcinoma HeLa cells, both responses being abrogated by Bcl-x(L) overexpression. We synthesized a number of new fluorescent edelfosine analogs, which preserved the proapoptotic activity of the parent drug, and colocalized with mitochondria in HeLa cells. Edelfosine induced swelling in isolated mitochondria, indicating an increase in mitochondrial membrane permeability. This mitochondrial swelling was independent of reactive oxygen species generation. A structurally related inactive analog was unable to promote mitochondrial swelling, highlighting the importance of edelfosine molecular structure in its effect on mitochondria. Raft disruption inhibited mitochondrial localization of the drug in cells and edelfosine-induced swelling in isolated mitochondria. Edelfosine promoted a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. Our data suggest that direct interaction of edelfosine with mitochondria eventually leads to mitochondrial dysfunction and apoptosis. These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment.
authors: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. fmollin@usal.es
authors: F
authors: F
authors: Mollinedo
authors: M
authors: M
authors: Fernández
authors: V
authors: V
authors: Hornillos
authors: J
authors: J
authors: Delgado
authors: F
authors: F
authors: Amat-Guerri
authors: A U
authors: AU
authors: Acuña
authors: T
authors: T
authors: Nieto-Miguel
authors: J A
authors: JA
authors: Villa-Pulgarín
authors: C
authors: C
authors: González-García
authors: V
authors: V
authors: Ceña
authors: C
authors: C
authors: Gajate
references: Cancer Res. 2007 Nov 1;67(21):10368-78
references: 17974980
references: Oncogene. 2006 Aug 7;25(34):4812-30
references: 16892093
references: Oncogene. 2010 Jul 1;29(26):3748-57
references: 20418917
references: J Biol Chem. 2005 Nov 11;280(45):38047-58
references: 16155007
references: Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1150-60
references: 15130918
references: Int J Cancer. 2000 Apr 15;86(2):208-18
references: 10738248
references: Clin Cancer Res. 2010 Apr 1;16(7):2046-54
references: 20233887
references: Biochem Biophys Res Commun. 2009 Mar 20;380(4):780-4
references: 19338752
references: FEBS Lett. 2010 Nov 19;584(22):4606-10
references: 20965172
references: Nature. 2008 Dec 4;456(7222):605-10
references: 19052620
references: J Biol Chem. 1990 Nov 5;265(31):18797-802
references: 2172233
references: Blood. 2001 Dec 15;98(13):3860-3
references: 11739199
references: J Biol Chem. 1992 Feb 15;267(5):2934-9
references: 1737749
references: J Clin Invest. 2002 Oct;110(7):891-8
references: 12370264
references: Mol Cell Biochem. 1998 Jul;184(1-2):379-91
references: 9746332
references: J Biol Chem. 2002 Oct 18;277(42):39541-7
references: 12183451
references: J Biol Chem. 2004 Oct 22;279(43):45226-34
references: 15316012
references: Cancer Res. 2008 Jul 1;68(13):5246-56
references: 18593925
references: Int J Cancer. 2000 Mar 1;85(5):674-82
references: 10699948
references: Apoptosis. 2007 May;12(5):841-55
references: 17453156
references: Cell Death Differ. 2005 Nov;12(11):1378-89
references: 15947792
references: Cell Death Differ. 2010 Jun;17(6):1047-58
references: 20075943
references: Blood. 2007 Jan 15;109(2):711-9
references: 17003375
references: PLoS One. 2009;4(4):e5044
references: 19352436
references: J Phys Chem B. 2008 Sep 18;112(37):11643-54
references: 18712919
references: J Bioenerg Biomembr. 2007 Feb;39(1):65-72
references: 17294131
references: FEBS Lett. 2009 Aug 6;583(15):2447-50
references: 19616549
references: J Exp Med. 2004 Aug 2;200(3):353-65
references: 15289504
references: Cancer Res. 1997 Apr 1;57(7):1320-8
references: 9102220
references: Mol Cell. 2009 Nov 13;36(3):500-11
references: 19917257
references: Eur J Biochem. 1989 Jul 15;183(1):179-87
references: 2546771
references: Biochim Biophys Acta. 2007 Sep;1768(9):2213-21
references: 17573036
references: J Biol Chem. 2006 May 26;281(21):14833-40
references: 16540473
references: J Chem Biol. 2008 Nov;1(1-4):89-94
references: 19568801
references: FEBS Lett. 1996 Apr 8;384(1):53-7
references: 8797802
references: Cancer Res. 1983 Jul;43(7):3197-202
references: 6850630
references: Br J Pharmacol. 2002 Dec;137(7):993-1000
references: 12429571
references: Curr Drug Metab. 2002 Oct;3(5):491-525
references: 12369895
references: Curr Med Chem. 2004 Dec;11(24):3163-84
references: 15579006