The sphingolipid ceramide, a bioeffector lipid, is known to regulate anti-proliferative and stress responses in various human cancer cells. Studies from this project have defined a novel pathway for the generation of ceramide, 'the salvage pathway', which involves activation of acid sphingomyelinase (aSMase). Interestingly, our preliminary results show that the cytotoxic agents cisplatin, doxorubicin, and paclitaxel exert significant effects on the adhesion and migration of cancer cells, at sub-toxic concentrations. Importantly, these results suggest an important role for the aSMase/ceramide pathway in regulating these responses. These data and insights lead us to the HYPOTHESIS that the aSMase/ceramide pathway is an important mediator of stress inducers, with key roles in regulating cell migration and metastasis. Therefore, 3 specific aims are proposed: 1) To define molecular mechanisms of activation of aSMase. We will focus on defining a) the role of PKC3 as an upstream kinase in regulation of aSMase;b) the biochemical and cellular mechanisms by which phosphorylation activates the enzyme;and c) the cellular compartment where aSMase is activated. 2) To determine the role of aSMase in tumor growth and metastasis and response to chemotherapy by: a) establishing the role of aSMase/ceramide in cell adhesion/migration of cancer cells;b) examining and defining the role of this pathway in tumor metastasis/growth in vivo. 3) To determine the mechanisms by which the aSMase/ceramide pathway mediates cell stress responses. Understanding this pathway should have great impact on the field of ceramide-mediated biology precisely by beginning to untangle the complexity of these pathways through provision of pathway-specific insight. Equally as important, defining upstream and downstream components of this pathway, which is activated by agents of significant therapeutic value, may result in defining novel therapeutic targets in cancer therapy. Finally, there is the tantalizing possibility that the role of this pathway in inhibition of cell migration in response to chemotherapeutic agents may lead to a re-examination of therapeutically relevant actions of these agents by focusing on their effects on migration and metastasis rather than on cytotoxicity or proliferation.
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