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.
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