Sphingosine Kinase 1 As an Anticancer Therapeutic Target

Overview

Journal Drug Des Devel Ther

Specialty Pharmacology

Date 2015 Jul 8

PMID 26150697

Citations 23

Authors

Ying Gao

Fei Gao

Kan Chen

Mei-li Tian

Dong-Li Zhao

Affiliations

Soon will be listed here.

Abstract

The development of chemotherapeutic resistance is a major challenge in oncology. Elevated sphingosine kinase 1 (SK1) levels is predictive of a poor prognosis, and SK1 overexpression may confer resistance to chemotherapeutics. The SK/sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor (S1PR) signaling pathway has been implicated in the progression of various cancers and in chemotherapeutic drug resistance. Therefore, SK1 may represent an important target for cancer therapy. Targeting the SK/S1P/S1PR signaling pathway may be an effective anticancer therapeutic strategy, particularly in the context of overcoming drug resistance. This review summarizes our current understanding of the role of SK/S1P/S1PR signaling in cancer and development of SK1 inhibitors.

Citing Articles

Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones.

Kruschel R, Malone K, Walsh A, Waeber C, McCarthy F Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006080 PMC: 11859825. DOI: 10.3390/ph18020268.

The Role of Sphingolipid Metabolism in Pregnancy-Associated Breast Cancer After Chemotherapy.

Blokhin V, Zavarykina T, Kotsuba V, Kapralova M, Gutner U, Shupik M Biomedicines. 2025; 12(12.

PMID: 39767749 PMC: 11673991. DOI: 10.3390/biomedicines12122843.

Nanoparticle co-delivery of carboplatin and PF543 restores platinum sensitivity in ovarian cancer models through inhibiting platinum-induced pro-survival pathway activation.

Wang C, Li Q, Song K, Wang W, Zhang N, Dai L Nanoscale Adv. 2024; 6(16):4082-4093.

PMID: 39114142 PMC: 11302180. DOI: 10.1039/d4na00227j.

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target.

Sami Alkafaas S, Elsalahaty M, Ismail D, Ali Radwan M, Samy ElKafas S, Loutfy S Cancer Cell Int. 2024; 24(1):89.

PMID: 38419070 PMC: 10903003. DOI: 10.1186/s12935-024-03221-8.

Effect of Quercetin and Fingolimod, Alone or in Combination, on the Sphingolipid Metabolism in HepG2 Cells.

Momchilova A, Nikolaev G, Pankov S, Vassileva E, Krastev N, Robev B Int J Mol Sci. 2022; 23(22).

PMID: 36430423 PMC: 9697772. DOI: 10.3390/ijms232213916.

References

Nagaoka Y, Otsuki K, Fujita T, Uesato S . Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast and colon cancer cells. Biol Pharm Bull. 2008; 31(6):1177-81. DOI: 10.1248/bpb.31.1177. View

Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G . Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010; 9(11):883-97. DOI: 10.1038/nrd3248. View

Leclercq T, Moretti P, Pitson S . Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis. Oncogene. 2010; 30(3):372-8. DOI: 10.1038/onc.2010.420. View

Davis M, Clemens J, Macdonald T, Lynch K . Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem. 2004; 280(11):9833-41. DOI: 10.1074/jbc.M412356200. View

Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S . Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat. 2007; 112(1):41-52. DOI: 10.1007/s10549-007-9836-9. View

Pchejetski D, Bohler T, Brizuela L, Sauer L, Doumerc N, Golzio M . FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 2010; 70(21):8651-61. DOI: 10.1158/0008-5472.CAN-10-1388. View

Zhang Y, Wang Y, Wan Z, Liu S, Cao Y, Zeng Z . Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PLoS One. 2014; 9(2):e90362. PMC: 3937388. DOI: 10.1371/journal.pone.0090362. View

Li T, Chen L . [Alphastatin inhibits tumor angiogenesis in nude mice bearing human gastric cancer xenografts]. Zhonghua Wei Chang Wai Ke Za Zhi. 2009; 12(1):61-4. View

Malavaud B, Pchejetski D, Mazerolles C, de Paiva G, Calvet C, Doumerc N . Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens. Eur J Cancer. 2010; 46(18):3417-24. DOI: 10.1016/j.ejca.2010.07.053. View

10.

Stahelin R, Hwang J, Kim J, Park Z, Johnson K, Obeid L . The mechanism of membrane targeting of human sphingosine kinase 1. J Biol Chem. 2005; 280(52):43030-8. DOI: 10.1074/jbc.M507574200. View

11.

Fisher K, Pop A, Koh W, Anthis N, Saunders W, Davis G . Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling. Mol Cancer. 2006; 5:69. PMC: 1762019. DOI: 10.1186/1476-4598-5-69. View

12.

Illuzzi G, Bernacchioni C, Aureli M, Prioni S, Frera G, Donati C . Sphingosine kinase mediates resistance to the synthetic retinoid N-(4-hydroxyphenyl)retinamide in human ovarian cancer cells. J Biol Chem. 2010; 285(24):18594-602. PMC: 2881785. DOI: 10.1074/jbc.M109.072801. View

13.

Akao Y, Banno Y, Nakagawa Y, Hasegawa N, Kim T, Murate T . High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun. 2006; 342(4):1284-90. DOI: 10.1016/j.bbrc.2006.02.070. View

14.

Van Brocklyn J, Jackson C, Pearl D, Kotur M, Snyder P, Prior T . Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol. 2005; 64(8):695-705. DOI: 10.1097/01.jnen.0000175329.59092.2c. View

15.

Pyne S, Edwards J, Ohotski J, Pyne N . Sphingosine 1-phosphate receptors and sphingosine kinase 1: novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers. Front Oncol. 2013; 2:168. PMC: 3540928. DOI: 10.3389/fonc.2012.00168. View

16.

Bektas M, Jolly P, Muller C, Eberle J, Spiegel S, Geilen C . Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene. 2005; 24(1):178-87. DOI: 10.1038/sj.onc.1208019. View

17.

Watson C, Long J, Orange C, Tannahill C, Mallon E, McGlynn L . High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients. Am J Pathol. 2010; 177(5):2205-15. PMC: 2966780. DOI: 10.2353/ajpath.2010.100220. View

18.

Bayerl M, Bruggeman R, Conroy E, Hengst J, King T, Jimenez M . Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions. Leuk Lymphoma. 2008; 49(5):948-54. DOI: 10.1080/10428190801911654. View

19.

Baran Y, Salas A, Senkal C, Gunduz U, Bielawski J, Obeid L . Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem. 2007; 282(15):10922-34. DOI: 10.1074/jbc.M610157200. View

20.

Yamashita H, Kitayama J, Shida D, Yamaguchi H, Mori K, Osada M . Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells: differential regulation on the migration and proliferation. J Surg Res. 2005; 130(1):80-7. DOI: 10.1016/j.jss.2005.08.004. View