Acid ceramidase (AC) is a key enzyme in the sphingolipid rheostat which controls the relationship between ceramide (Cer) and sphingosine (Sph) sphingosine-1-phosphate (S1P) in the cell. Ceramide is associated with cell cycle control and apoptosis, and is thusly termed a tumor suppressor lipid. S1P promotes an antiapoptotic phenotype associated with improved angiogenesis, growth and metastasis. Thus, the balance of these two sphingolipids is very important in dictating cellular death or survival. Acid ceramidase is intimately involved in regulation of the pathway by deacylation of Cer forming Sph, the substrate of sphingosine kinase (SK1) which catalyses formation of S1P. Over-expression of SK1 has been shown to be oncogenic, making it by definition intimately involved in regulation of cell fate and/or development of cancer. In published studies, we have demonstrated that AC over-expression in prostate cancer (PCa) cells promotes cancer cell growth, migration, adhesion and mediates resistance to doxorubicin, taxol, etoposide, gemcitabine and cisplatin. This is therefore highly relevant to human cancer since >60% of Gleason grade 5-6 and 80% of Gleason grade 8-10 prostate cancers over-express AC. This leads to the long-term objective of this project which is to understand the consequences of AC up-regulation on progression and metastasis of prostate cancer (PCa) and determine how AC contributes to chemotherapy resistance. From a therapeutic view point, we believe that down-regulation of AC may play a role favoring pro-apoptosis by shifting the balance toward ceramide and away from S1P in tumors. We will examine this in three specific aims.
The first aim will firmly establish that AC is over-expressing in primary PCa tissues compared to adjacent controls and to determine the clinical relevance of this observation.
The second aim will be to determine the functional consequence of AC over-expression on PCa biology. The third specific aim will determine the role of AC in resistance to chemotherapy and if inhibition of AC promotes a therapeutic response in vivo. Taken together, we believe these studies will identify AC as a major prognosticator for therapeutic outcomes in PCa clinical therapy. This information will be used to develop therapeutic strategies to improve PCa therapy with the intention of translating this to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA097132-10
Application #
8381025
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$218,756
Indirect Cost
$42,423
Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Chen, Jennifer Y; Newcomb, Benjamin; Zhou, Chan et al. (2017) Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep 7:44867
Janecke, Andreas R; Xu, Ruijuan; Steichen-Gersdorf, Elisabeth et al. (2017) Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat 38:365-372
Xu, Ruijuan; Garcia-Barros, Monica; Wen, Sally et al. (2017) Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. Cell Death Differ :
Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2017) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul 63:140-155
McCracken, A N; McMonigle, R J; Tessier, J et al. (2017) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia 31:669-677
Pulkoski-Gross, Michael J; Uys, Joachim D; Orr-Gandy, K Alexa et al. (2017) Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis. Prostaglandins Other Lipid Mediat 130:47-56
Coant, Nicolas; Sakamoto, Wataru; Mao, Cungui et al. (2017) Ceramidases, roles in sphingolipid metabolism and in health and disease. Adv Biol Regul 63:122-131
Hernández-Corbacho, María José; Salama, Mohamed F; Canals, Daniel et al. (2017) Sphingolipids in mitochondria. Biochim Biophys Acta 1862:56-68
Bai, Aiping; Mao, Cungui; Jenkins, Russell W et al. (2017) Anticancer actions of lysosomally targeted inhibitor, LCL521, of acid ceramidase. PLoS One 12:e0177805
Lin, Chih-Li; Xu, Ruijuan; Yi, Jae Kyo et al. (2017) Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells. Stem Cell Reports 9:1488-1500

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