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 ceramide functions as a tumor suppressor lipid, that can regulate apoptosis, senescence, and/or migration. As such, pathways of ceramide metabolism play key roles in cancer pathobiology and the response to anti-cancer and other stress agents. On the other hand, the sphingolipid sphingosine-1-phosphate (S1P) is emerging as a tumor promoting lipid with anti-apoptotic, antisenescence, pro-migration, and pro-angiogenic functions. The study of bioactive lipids is fraught with difficulties and thus necessitates the collaborative interactions of various disciplines and specialized cores. Thus, the overall hypothesis will be approached through the activities of 4 distinct projects: Project 1 will address the specific hypothesis that the acid sphingomyelinase/ceramide pathway is an important mediator of stress inducers, with key roles in regulating cancer cell migration. Project 2 will test the specific hypothesis that acid ceramidase plays an important role in controlling the dynamic balance of cellular levels of ceramide and S1P with direct consequences for novel anti-cancer therapeutics. Project 3 will test the hypothesis that sphingosine kinase 1 (SK1) proteolysis/knock-down mediates, at least part of, p53 tumor suppressor function, and that the SK1/S1P pathway mediates/participates in null/mutant p53-induced cancer. Project 4 will test the hypothesis that that LASS6-generated C16-(dihydro)ceramide plays important roles in the regulation of ER homeostasis, such that down-regulation of this pathway mediates a significant component of the ER stress response. These 4 projects will be supported by an Administrative Core, by a unique Lipidomics Core that will provide analytical and synthetic lipid chemistry, and by an Animal Core that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of carcinogenesis. The results from 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 biology and therapeutics. Ongoing studies have already resulted in the identification of novel strategies for cancer therapeutics based on novel sphingolipid-based compounds that target specific enzymes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA097132-08S1
Application #
8132635
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Ogunbiyi, Peter
Project Start
2002-07-01
Project End
2013-07-31
Budget Start
2010-08-17
Budget End
2011-07-31
Support Year
8
Fiscal Year
2010
Total Cost
$39,388
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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
Ren, Jihui; Snider, Justin; Airola, Michael V et al. (2018) Quantification of 3-ketodihydrosphingosine using HPLC-ESI-MS/MS to study SPT activity in yeast Saccharomyces cerevisiae. J Lipid Res 59:162-170
Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M et al. (2018) Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. Carcinogenesis 39:47-55
Carroll, Brittany L; Bonica, Joseph; Shamseddine, Achraf A et al. (2018) A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway. FEBS Open Bio 8:27-40
Xu, Ruijuan; Garcia-Barros, Monica; Wen, Sally et al. (2018) Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. Cell Death Differ 25:841-856
Coant, Nicolas; Hannun, Yusuf A (2018) Neutral ceramidase: Advances in mechanisms, cell regulation, and roles in cancer. Adv Biol Regul :
Trayssac, Magali; Hannun, Yusuf A; Obeid, Lina M (2018) Role of sphingolipids in senescence: implication in aging and age-related diseases. J Clin Invest 128:2702-2712
Munshi, Mansa A; Gardin, Justin M; Singh, Ashutosh et al. (2018) The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus neoformans. Cell Rep 22:1392-1400
Snider, Justin M; Snider, Ashley J; Obeid, Lina M et al. (2018) Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry. J Lipid Res 59:1046-1057
Li, Fang; Xu, Ruijuan; Low, Benjamin E et al. (2018) Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates. FASEB J 32:3058-3069

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