Pathways of sphingolipid metabolism provide a very rich network of bioactive molecules whose emerging functions suggest key roles in the regulation of cell function. In particular, published and preliminary results suggest the global hypothesis that pathways linked to ceramide formation play key roles in cytokine- and chemotherapy-induced cancer cell death whereas the sphingolipid sphingosine-l-phosphate (SIP) may emerge as a key and novel regulator of tumor neo-vascularization. This overall hypothesis will be approached through the activities of 3 distinct projects: Project 1 will address the specific hypothesis that the de novo synthesis of ceramide and sphingomyelin hydrolysis define two distinct pathways of ceramide formation which mediate synergistic tumor cell death through two distinct mechanisms. Project 2 will test the specific hypothesis that the ability to sensitize uninfected and/or resistant tumor cells (by addition of antisense molecules, chemotherapy, or agents that induce ceramide levels), would promote a more proapoptotic phenotype, and this would facilitate bystander activity and achieve greater tumor cell killing. Project 3 will test the hypothesis that sphingosine kinase and its product SIP regulate tumor angiogenesis, and inhibiting this pathway could inhibit tumor angiogenesis. These 3 projects will be supported by an Administrative Core and by a unique Lipidomics Core that will provide analytical and synthetic lipid chemistry. The results of these interactive studies would bring this last frontier of cellular biochemistry (sphingolipid metabolism) into cancer biology research, generating significant and unique insights into cancer cell death and tumor angiogenesis. The studies should also result in the identification of novel strategies for cancer therapeutics aimed at inducing cancer cell death and/or inhibition of tumor angiogenesis.
| Pulkoski-Gross, Michael J; Jenkins, Meredith L; Truman, Jean-Philip et al. (2018) An intrinsic lipid-binding interface controls sphingosine kinase 1 function. J Lipid Res 59:462-474 |
| Williams, Bianca; Correnti, Jason; Oranu, Amanke et al. (2018) A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. FASEB J 32:130-142 |
| Bai, Aiping; Bielawska, Alicja; Rahmaniyan, Mehrdad et al. (2018) Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites. Bioorg Med Chem 26:6067-6075 |
| Newcomb, Benjamin; Rhein, Cosima; Mileva, Izolda et al. (2018) Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5. J Lipid Res 59:1219-1229 |
| Espaillat, Mel Pilar; Snider, Ashley J; Qiu, Zhijuan et al. (2018) Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. FASEB J 32:2339-2353 |
| Hannun, Yusuf A; Obeid, Lina M (2018) Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19:175-191 |
| Schwartz, Nicholas U; Linzer, Ryan W; Truman, Jean-Philip et al. (2018) Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. FASEB J 32:1716-1728 |
| Moorthi, Sitapriya; Burns, Tara Ann; Yu, Gui-Qin et al. (2018) Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation. FASEB J 32:4270-4283 |
| Morris, Thomas G; Borland, Samantha J; Clarke, Christopher J et al. (2018) Sphingosine 1-phosphate activation of ERM contributes to vascular calcification. J Lipid Res 59:69-78 |
| Coant, Nicolas; García-Barros, Mónica; Zhang, Qifeng et al. (2018) AKT as a key target for growth promoting functions of neutral ceramidase in colon cancer cells. Oncogene 37:3852-3863 |
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