My talk presenting my thesis work per invitation of Research and Development Division of Genzyme Corporation to the Lipid Storage Disorders Department. October 5, 2007. Boston, MA: "Sphingosine 1-phosphate Receptor Subtype Influence over Glioblastoma Multiforme Pathology". My PhD was earned through the Integrated Biomedical Sciences, September 2007, The Ohio State University, College of Medicine Columbus, OH. Area of focus for my PhD: Biochemical and Molecular Disease Mechanisms. Dissertation title: Sphingosine 1-phosphate Receptor Subtype Influence Over Glioblastoma Multiforme Malignant Behavior"
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Nicholas Young, Sphingosine 1-phosphate Receptor Subtype Influence over Glioblastoma Multiforme Pathology
1. INFLUENCE OF SPHINGOSINE 1-PHOSPHATE RECEPTOR SUBTYPES OVER GLIOBLASTOMA MULTIFORME MALIGNANT BEHAVIOR Nicholas Young, Integrated Biomedical Science Graduate Program
25. U118-MG Gelatin Matrigel Well Coating Serum free media Serum free media + 100nm S1P Adhesion Assay * * * * * # #
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27. Relationship between G-protein signaling to cellular motility and invasiveness Gi Rac Lamellapodia formation Rho Stress fiber formation G 12/13 PTX Y-27632 ROCK Gi and G12/13 couple to the small GTPases Rho and Rac - results in actin cytoskeleton rearrangements 1. How do the S1P receptor subtypes influence Rho and Rac activation? 2. How does this influence actin cytoskeletal rearrangement? 3. Does Rho/Rac activation influence migratory and invasive response? S1P 2 ?
52. SK inhibitor - + - + - + - + Cntrl S1P 1 S1P 3 S1P 2 SK inhibitor - + - + - + - + Cntrl S1P 1 S1P 3 S1P 2 uPAR GAPDH uPA activity Cntrl * SK activity (pmol/min/mg protein) sphingosine kinase inhibitor and its effects on uPAR expression and uPA activity U-118 MG
53. Cntrl S1P1 Day Cellular viability (%) sphingosine kinase inhibitor and its effects on cellular viability
54. cntrl S1P 1 U-118 MG DMSO SK sicntrl siSK siSK inh A B uPA activity DMSO SK sicntrl siSK siSK inh A B siRNA to SK mimics sphingosine kinase inhibitor in reducing uPA activation
58. 4x 10x 20x 40x SF S1P cAb uPA Ab CCN1 Ab SK inh S1P 1 cellular morphology along the invasive periphery during spheroid invasion
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61. SK-1 SK-1 sph S1P S1P S1PR Rac MOTILITY INVASION ERK AKT SURVIVAL GROWTH CCN1 uPA 3 v pro- uPA CCN1 CCN1 CCN1 v v 3 3 (ECM) ADHESION uPAR (Endothelial cell Recruitement) ANGIOGENESIS plasminogen plasmin INVASION uPAR uPAR uPA pro- uPA pro- uPA matriptase CCN1 Ab uPA Ab SK inh
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63. X-12 U-87 MG Invasion of human glioma cells into surrounding mouse brain
64. S1P-induced spheroid invasion in neuronal stem cells and X-12 glioma cells Neuronal stem cell line SFME and X-12 glioma cell line were grown in defined media to enrich stem-like cancer cells as neurospheres
70. “ An expert is a man who has made all the mistakes which can be made, in a narrow field.” Niels Bohr (1885-1962) “ Everything should be as simple as it is, but not simpler.” Albert Einstein (1879-1955) “ When you steal from one author, it's plagiarism; if you steal from many, it's research.” Wilson Mizner (1876-1933)
72. cntrl S1P 1 S1P 2 S1P 3 Day Day Day Day Invasive diameter – core diameter ( m) Invasive diameter – core diameter ( m) Invasive diameter – core diameter ( m) Invasive diameter – core diameter ( m) inhibition of spheroid invasiveness with SK inhibitor and uPA/CCN1 ab U-118 MG cells
73. S1P + + + + + + I P Cntrl S1P1 S1P2 I D Cntrl S1P1 S1P2 - plasminogen S1P - + - + - + - + Cntrl S1P 1 S1P 3 S1P 2 uPA activity uPA activity uPA activity is not nonspecific and can be immunoprecipitated