Sphingosine kinase mediates resistance to the synthetic retinoid N-(4-hydroxyphenyl)retinamide in human ovarian cancer cells.
A2780 human ovarian carcinoma cells respond to treatment with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) with the production of dihydroceramide and with a concomitant reduction of cell proliferation and induction of apoptosis. The derived HPR-resistant clonal cell line, A2780/HPR, is less responsive to HPR in terms of dihydroceramide generation. In this report, we show that the production of sphingosine 1-phosphate (S1P) is significantly higher in A2780/HPR versus A2780 cells due to an increased sphingosine kinase (SK) activity and SK-1 mRNA and protein levels. Treatment of A2780 and A2780/HPR cells with a potent and highly selective pharmacological SK inhibitor effectively reduced S1P production and resulted in a marked reduction of cell proliferation. Moreover, A2780/HPR cells treated with a SK inhibitor were sensitized to the cytotoxic effect of HPR, due to an increased dihydroceramide production. On the other hand, the ectopic expression of SK-1 in A2780 cells was sufficient to induce HPR resistance in these cells. Challenge of A2780 and A2780/HPR cells with agonists and antagonists of S1P receptors had no effects on their sensitivity to the drug, suggesting that the role of SK in HPR resistance in these cells is not mediated by the S1P receptors. These data clearly demonstrate a role for SK in determining resistance to HPR in ovarian carcinoma cells, due to its effect in the regulation of intracellular ceramide/S1P ratio, which is critical in the control of cell death and proliferation.
Illuzzi
Giuditta
G
Department of Medical Chemistry, University of Milan, Center of Excellence on Neurodegenerative Diseases, 20090 Segrate, Italy.
Bernacchioni
Caterina
C
Aureli
Massimo
M
Prioni
Simona
S
Frera
Gianluca
G
Donati
Chiara
C
Valsecchi
Manuela
M
Chigorno
Vanna
V
Bruni
Paola
P
Sonnino
Sandro
S
Prinetti
Alessandro
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000099157:Sphingosine Kinase
D000970:Antineoplastic Agents; D017313:Fenretinide; D008055:Lipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D000099157:Sphingosine Kinase
Mol Cancer Ther. 2004 May;3(5):633-9
15141021
J Histochem Cytochem. 2001 Jul;49(7):845-55
11410609
Br J Cancer. 2001 Jun 1;84(11):1528-34
11384104
Mol Cancer Ther. 2008 Sep;7(9):2967-76
18790777
Apoptosis. 2006 Oct;11(10):1677-94
16850162
FEBS Lett. 2007 Sep 18;581(23):4384-8
17719579
Glia. 2006 Apr 15;53(6):621-30
16470810
J Lipid Res. 2009 Apr;50 Suppl:S97-102
19029065
Biochim Biophys Acta. 2008 Sep;1781(9):442-7
18638570
Exp Cell Res. 2006 Apr 15;312(7):1164-73
16527273
J Biol Chem. 2003 Feb 21;278(8):5574-83
12486134
Urology. 2003 May;61(5):1047-52
12736045
J Biol Chem. 2003 Nov 21;278(47):46452-60
12963721
J Lipid Res. 2007 Feb;48(2):417-24
17093290
J Biol Chem. 2000 Oct 27;275(43):33945-50
10944534
J Lipid Res. 2010 Jul;51(7):1832-40
20194109
Cancer Res. 2001 Jul 1;61(13):5102-5
11431347
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1284-90
16516161
J Biol Chem. 2007 Jun 8;282(23):16718-28
17283068
FASEB J. 2001 Mar;15(3):719-30
11259390
J Biol Chem. 1999 Jan 8;274(2):1140-6
9873062
Mol Cancer Res. 2009 Mar;7(3):393-401
19240180
Nature. 1998 Oct 22;395(6704):801-4
9796814
Anal Biochem. 1994 Dec;223(2):306-12
7887476
Mol Cancer Ther. 2008 Jul;7(7):1836-45
18644996
Biochim Biophys Acta. 2006 Dec;1758(12):2096-103
17010304
J Biol Chem. 2003 Nov 21;278(47):46832-9
12954646
Mol Cancer Ther. 2009 Apr;8(4):809-20
19372554
Science. 1996 Dec 13;274(5294):1855-9
8943189
Methods. 2001 Dec;25(4):402-8
11846609
J Lipid Res. 2004 May;45(5):933-40
14967819
Methods Enzymol. 2000;311:656-82
10563354
Cell. 1994 May 6;77(3):325-8
8181053
J Biol Chem. 2009 Apr 17;284(16):10422-32
19240026
Biochim Biophys Acta. 2006 Dec;1758(12):1864-84
17052686
Expert Rev Anticancer Ther. 2007 Apr;7(4):423-32
17428163
Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1454-61
18535287
J Neurooncol. 2002 Mar;57(1):27-36
12125964
J Biol Chem. 1951 Nov;193(1):265-75
14907713