SPHINGOSINE KINASE AND CANCER

Summary

Principal Investigator: S Spiegel
Affiliation: Virginia Commonwealth University
Country: USA
Abstract: Aberrant regulation of growth and apoptosis, important factors in development of cancer, have recently been linked to the sphingolipid metabolites, ceramide and sphingosinel-phosphate (SPP). Whereas ceramide has been associated with cell growth arrest and apoptosis, SPP, a further metabolite of ceramide, is a growth promoter and survival factor. Ample evidence indicates that SPP, formed by activation of sphingosine kinase (SPHK), can serve as an intracellular second messenger which modulates pathways important for cell growth, motility, and survival. Moreover, because SPP antagonizes apoptosis mediated by ceramide, a stress-induced sphingolipid metabolite, we have suggested that the intracellular ratio of these two sphingolipids metabolites and consequent regulation of opposing signaling pathways, is an important factor that determines whether a cell survives or dies. It is our hypothesis that the novel lipid kinase, SPHK, which produces SPP, acting in an analogous manner to the well known actions of P13-kinase, also plays a pivotal role in regulation of proliferation, survival, and motility. In this proposal, we will examine the role of SPHK in resistance of cancer cells to apoptosis and determine potential interactions of SPHK, and its product SPP, with signaling pathways known to be involved in initiation and/or execution phases of apoptosis. Expression of SPHK not only enhances cell proliferation, but surprisingly, it inhibits motility, suggesting that SPHK may play a critical role in several biological processes affecting cancer. Our understanding of how SPHK kinase achieves its spectrum of cellular effects is rudimentary and the challenge ahead is to elucidate the hierarchical relationships between SPHK and downstream signaling and establish whether overlapping or unique signaling pathways are involved in processes regulating growth and motility of cancer cells. Remarkably, SPHK, whose activity we have shown is regulated by various stimuli, is devoid of recognizable regulatory motifs suggesting that additional components remain to be discovered. We will attempt to identify potential SPHK interacting proteins which might be important for signaling, regulation, subcellular localization, or assembly of intracellular signaling complexes Although a number of potential indirect targets of SPP have been described, to date, the bona fide direct intracellular targets for SPP are still unknown and this will be another focus of this proposal. Our studies promise great rewards in deciphering its mechanisms of action and should help to fill in the gaps linking SPP to known intracellular signaling pathways and will enhance our understanding of how these regulated pathways of sphingolipid metabolism fit into the important areas of growth regulation, survival, and cancer biology.
Funding Period: 1994-06-01 - 2005-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression
    Meryem Bektas
    Department of Dermatology, Charite Universitatsmedizin Berlin, Campus Benjamin Franklin, Fabeckstr 60 62, Berlin 14195, Germany
    Oncogene 24:178-87. 2005
  2. ncbi Autocrine and paracrine roles of sphingosine-1-phosphate
    Sergio E Alvarez
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Trends Endocrinol Metab 18:300-7. 2007
  3. ncbi Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin
    Heidi M Sankala
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298 0614, USA
    Cancer Res 67:10466-74. 2007
  4. pmc Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells
    Adly Yacoub
    Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298 0035, USA
    Mol Cancer Ther 7:297-313. 2008
  5. pmc Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal
    David R Gude
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, VCU School of Medicine, 1101 E Marshall St, Richmond, VA 23298, USA
    FASEB J 22:2629-38. 2008
  6. pmc Cross-talk at the crossroads of sphingosine-1-phosphate, growth factors, and cytokine signaling
    Deborah A Lebman
    Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    J Lipid Res 49:1388-94. 2008
  7. pmc Regulation and functions of sphingosine kinases in the brain
    Lauren Bryan
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Biochim Biophys Acta 1781:459-66. 2008
  8. pmc A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia
    Steven W Paugh
    Departments ofBiochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298 0614, USA
    Blood 112:1382-91. 2008
  9. pmc "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets
    Kazuaki Takabe
    Department of Surgery, Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Pharmacol Rev 60:181-95. 2008
  10. pmc Filamin A links sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 at lamellipodia to orchestrate cell migration
    Michael Maceyka
    Department of Biochemistry and Molecular Biology, VCU School of Medicine, P O Box 980614, 1101 E Marshall St, Richmond, VA 23298 0614, USA
    Mol Cell Biol 28:5687-97. 2008

Scientific Experts

  • Sylvie Coursol
  • S Spiegel
  • Charles Chalfant
  • Sheldon Milstien
  • Nitai C Hait
  • Michael Maceyka
  • Tomasz Kordula
  • Steven W Paugh
  • Dmitri Kapitonov
  • Paul Dent
  • Steven Grant
  • Roberto R Rosato
  • Kazuaki Takabe
  • Lauren Bryan
  • Dai Shida
  • Sergio E Alvarez
  • Meryem Bektas
  • Barbara S Paugh
  • Jorge A Almenara
  • Shawn G Payne
  • Sukumar Sarkar
  • Mohamed Rahmani
  • Roger H Kim
  • Sandeep K Singh
  • Robert E Zipkin
  • Jeffrey K Adams
  • Katarzyna M Wilczynska
  • David R Gude
  • Adly Yacoub
  • Deborah A Lebman
  • Sandrine Lepine
  • Heidi M Sankala
  • Sonia C Maggio
  • Peter Atadja
  • Hervé Le Stunff
  • Farida Safadi-Chamberlain
  • Hong Liu
  • Heidi Sankala
  • Sravan K Goparaju
  • Puneet S Jolly
  • Jeremy C Allegood
  • Cheng Luo
  • Jeremy Allegood
  • Ronen Marmorstein
  • Clint Mitchell
  • Kuzhuvelil B Harikumar
  • GRAHAM M STRUB
  • Nicollaq Vozhilla
  • Rachael Griffiths
  • Luni Emdad
  • Margaret A Park
  • Devanand Sarkar
  • JiaDe Yu
  • Hanna Rokita
  • Irina V Lebedeva
  • David T Curiel
  • David Hanna
  • Martin Graf
  • Xianjun Fang
  • Silvina M Alvarez
  • Hossein Hamed
  • Mohammed Rahmani
  • Moira Sauane
  • Paul B Fisher
  • Poulami Mitra
  • Suzanne E Barbour
  • Guo Zhang
  • Sunita M Gopalan
  • Costas Koumenis
  • Pankaj Gupta
  • Lynne W Elmore
  • Andrea Bellamy
  • Carole A Oskeritzian
  • Christoph C Geilen
  • Julie Vrana
  • Michael H Fox
  • Rachelle Toman
  • Jürgen Eberle
  • Jerold Chun
  • Leslie S Satin
  • Scott A Summers
  • Alfred H Merrill
  • Kenneth R Watterson
  • Lin Mel
  • Ruth Craig
  • Isao Ishii
  • Sravan Goparaju
  • Li Ping Wang
  • Carola Müller
  • Aki Mikami

Detail Information

Publications35

  1. ncbi Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression
    Meryem Bektas
    Department of Dermatology, Charite Universitatsmedizin Berlin, Campus Benjamin Franklin, Fabeckstr 60 62, Berlin 14195, Germany
    Oncogene 24:178-87. 2005
    ..This link between Bcl-2 and SphK1 might be an additional clue to chemotherapy resistance of malignant melanoma...
  2. ncbi Autocrine and paracrine roles of sphingosine-1-phosphate
    Sergio E Alvarez
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Trends Endocrinol Metab 18:300-7. 2007
    ..This review summarizes recent findings on the roles of S1P as a mediator of the actions of cytokines, growth factors and hormones...
  3. ncbi Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin
    Heidi M Sankala
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298 0614, USA
    Cancer Res 67:10466-74. 2007
    ..Collectively, our results show that endogenous SphK2 is important for p53-independent induction of p21 expression by doxorubicin and suggest that SphK2 may influence the balance between cytostasis and apoptosis of human cancer cells...
  4. pmc Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells
    Adly Yacoub
    Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298 0035, USA
    Mol Cancer Ther 7:297-313. 2008
    ....
  5. pmc Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal
    David R Gude
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, VCU School of Medicine, 1101 E Marshall St, Richmond, VA 23298, USA
    FASEB J 22:2629-38. 2008
    ..Collectively, our data suggest that apoptotic cells may up-regulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis...
  6. pmc Cross-talk at the crossroads of sphingosine-1-phosphate, growth factors, and cytokine signaling
    Deborah A Lebman
    Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    J Lipid Res 49:1388-94. 2008
    ..This review discusses the mechanisms involved in cross-talk between S1P, cytokines, and growth factors and the impact of that cross-talk on cell signaling and cell biology...
  7. pmc Regulation and functions of sphingosine kinases in the brain
    Lauren Bryan
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Biochim Biophys Acta 1781:459-66. 2008
    ....
  8. pmc A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia
    Steven W Paugh
    Departments ofBiochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298 0614, USA
    Blood 112:1382-91. 2008
    ..Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia...
  9. pmc "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets
    Kazuaki Takabe
    Department of Surgery, Division of Surgical Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Pharmacol Rev 60:181-95. 2008
    ....
  10. pmc Filamin A links sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 at lamellipodia to orchestrate cell migration
    Michael Maceyka
    Department of Biochemistry and Molecular Biology, VCU School of Medicine, P O Box 980614, 1101 E Marshall St, Richmond, VA 23298 0614, USA
    Mol Cell Biol 28:5687-97. 2008
    ....
  11. pmc Targeting SphK1 as a new strategy against cancer
    Dai Shida
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, 1101 E Marshall Street, 2011 Sanger Hall, Richmond, VA 23298, USA
    Curr Drug Targets 9:662-73. 2008
    ..We will also review studies on the effects of SphK inhibitors in cells in vitro and in animals in vivo and in some clinical trials and highlight the potential of SphK1 as a new target for cancer therapeutics...
  12. pmc Cross-talk between LPA1 and epidermal growth factor receptors mediates up-regulation of sphingosine kinase 1 to promote gastric cancer cell motility and invasion
    Dai Shida
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0614, USA
    Cancer Res 68:6569-77. 2008
    ....
  13. pmc Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness
    Lauren Bryan
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Mol Cancer Res 6:1469-77. 2008
    ..Collectively, these results indicate that S1P and IL-1 activate distinct pathways leading to the mRNA and protein expression of PAI-1 and uPAR, which are important for glioblastoma invasiveness...
  14. pmc Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling
    Michael Maceyka
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    J Lipid Res 50:S272-6. 2009
    ....
  15. pmc Export and functions of sphingosine-1-phosphate
    Roger H Kim
    Division of Surgical Oncology, Department of Surgery and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
    Biochim Biophys Acta 1791:692-6. 2009
    ..In this review, we will discuss how S1P is formed and released. We will focus particularly on the current knowledge of how the S1P gradient between tissues and blood is maintained, and the role of ABC transporters in S1P release...
  16. pmc Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts
    Dmitri Kapitonov
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0614, USA
    Cancer Res 69:6915-23. 2009
    ..Our results support the notion that SphK1 may be an important factor in GBM and suggest that an isozyme-specific inhibitor of SphK1 deserves consideration as a new therapeutic agent for this disease...
  17. pmc EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells
    Barbara S Paugh
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine Massey Cancer Center, Richmond, VA 23298, USA
    FASEB J 22:455-65. 2008
    ..Collectively, our results provide a functional link between three critical downstream targets of EGF, c-Src, PKCdelta, and SphK1 that have all been implicated in regulating motility and invasion of glioma cells...
  18. ncbi Sphingosine kinase type 2 activation by ERK-mediated phosphorylation
    Nitai C Hait
    Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
    J Biol Chem 282:12058-65. 2007
    ....
  19. ncbi Functions of the multifaceted family of sphingosine kinases and some close relatives
    Sarah Spiegel
    Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
    J Biol Chem 282:2125-9. 2007
  20. pmc Arabidopsis sphingosine kinase and the effects of phytosphingosine-1-phosphate on stomatal aperture
    Sylvie Coursol
    Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802 5301, USA
    Plant Physiol 137:724-37. 2005
    ....
  21. pmc Effect of a membrane-targeted sphingosine kinase 1 on cell proliferation and survival
    Farida Safadi-Chamberlain
    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523 1870, USA
    Biochem J 388:827-34. 2005
    ..Collectively, these findings reveal that altering the subcellular location of SK1 has marked effects on cell function, with plasma membrane-associated SK having a potent inhibitory effect on the G1-S phase transition...
  22. ncbi Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species
    Mohamed Rahmani
    Department of Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
    Cancer Res 65:2422-32. 2005
    ..They also raise the possibility that combining these agents may represent a novel antileukemic strategy...
  23. pmc The S1P2 receptor negatively regulates platelet-derived growth factor-induced motility and proliferation
    Sravan K Goparaju
    Department of Biochemistry, Virginia Commonwealth University Medical Center, 1101 E Marshall Street, Room 2 011, Sanger Hall, Richmond, VA 23298 0614, USA
    Mol Cell Biol 25:4237-49. 2005
    ..Thus, S1P(2) serves as a negative regulator of PDGF-induced migration and proliferation as well as SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions...
  24. pmc A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells
    Meryem Bektas
    Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    J Cell Biol 169:801-11. 2005
    ..Hence, AGK can amplify EGF signaling pathways and may play an important role in the pathophysiology of prostate cancer...
  25. ncbi Role of sphingosine kinase 2 in cell migration toward epidermal growth factor
    Nitai C Hait
    Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, 23298, USA
    J Biol Chem 280:29462-9. 2005
    ..Our results suggest that SphK2 plays an important role in migration of MDA-MB-453 cells toward EGF...
  26. ncbi Histone deacetylase inhibitors: insights into mechanisms of lethality
    Roberto R Rosato
    Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298, USA
    Expert Opin Ther Targets 9:809-24. 2005
    ....
  27. ncbi Sphingosine kinases, sphingosine-1-phosphate and sphingolipidomics
    Michael Maceyka
    Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Prostaglandins Other Lipid Mediat 77:15-22. 2005
    ..Here, we briefly discuss the importance of LC-MS/MS for measuring sphingolipid metabolites and some future directions researchers may take given the increasingly accessibility to this technology...
  28. ncbi SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism
    Michael Maceyka
    Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
    J Biol Chem 280:37118-29. 2005
    ..Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of sphingosine 1-phosphate production dictates its functions...
  29. ncbi The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide
    Roberto R Rosato
    Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
    Mol Pharmacol 69:216-25. 2006
    ....
  30. ncbi Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells
    Sukumar Sarkar
    Department of Biochemistry, Virginia Commonwealth University, School of Medicine, Richmond, 23298 0614, USA
    FEBS Lett 579:5313-7. 2005
    ..These results suggest that SphK1 may be critical for growth, metastasis and chemoresistance of human breast cancers...
  31. ncbi Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling
    Charles E Chalfant
    Department of Biochemistry, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA
    J Cell Sci 118:4605-12. 2005
    ..S1P probably also has intracellular targets, and in plants it appears to directly regulate the G protein alpha subunit GPA1...
  32. ncbi Critical role of acylglycerol kinase in epidermal growth factor-induced mitogenesis of prostate cancer cells
    S Spiegel
    Department of Biochemistry, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA
    Biochem Soc Trans 33:1362-5. 2005
    ....
  33. ncbi Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells
    Roberto R Rosato
    Department of Medicine, Virginia Commonwealth University Medical College of Virginia, MCV Station Box 230, Richmond, VA 23298, USA
    Mol Cancer Ther 4:1772-85. 2005
    ....
  34. ncbi Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases
    Nitai C Hait
    Department of Biochemistry, Virginia Commonwealth University School of Medicine, 1101 E Marshall St, Richmond, VA 23298 0614, USA
    Biochim Biophys Acta 1758:2016-26. 2006
    ..Here we review the growing recent literature on the regulation and the roles of SphKs and S1P in apoptosis and diseases...
  35. pmc Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate
    Nitai C Hait
    Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Science 325:1254-7. 2009
    ..Thus, HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression...