Acid ceramidase (AC) is a key enzyme in the sphingolipid rheostat which controls the relationship betweenceramide (Cer) and sphingosine (Sph) sphingosine-1-phosphate (S1P) in the cell. Ceramide is associatedwith cell cycle control and apoptosis, and is thusly termed a tumor suppressor lipid. S1P promotes an antiapoptoticphenotype associated with improved angiogenesis, growth and metastasis. Thus, the balance ofthese two sphingolipids is very important in dictating cellular death or survival. Acid ceramidase is intimatelyinvolved 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, makingit 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) cellspromotes 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 grade5-6 and 80% of Gleason grade 8-10 prostate cancers over-express AC. This leads to the long-term objectiveof this project which is to understand the consequences of AC up-regulation on progression and metastasisof prostate cancer (PCa) and determine how AC contributes to chemotherapy resistance. From atherapeutic view point, we believe that down-regulation of AC may play a role favoring pro-apoptosis byshifting the balance toward ceramide and away from S1P in tumors. We will examine this in three specificaims.
The first aim will firmly establish that AC is over-expressing in primary PCa tissues compared toadjacent controls and to determine the clinical relevance of this observation.
The second aim will be todetermine the functional consequence of AC over-expression on PCa biology. The third specific aim willdetermine the role of AC in resistance to chemotherapy and if inhibition of AC promotes a therapeuticresponse in vivo. Taken together, we believe these studies will identify AC as a major prognosticator fortherapeutic outcomes in PCa clinical therapy. This information will be used to develop therapeutic strategiesto improve PCa therapy with the intention of translating this to the clinic.
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