The sphingolipid ceramide, a bioeffector lipid, is known to regulate anti-proliferative and stress responses invarious human cancer cells. Studies from this project have defined a novel pathway for the generation ofceramide, 'the salvage pathway', which involves activation of acid sphingomyelinase (aSMase). Interestingly,our preliminary results show that the cytotoxic agents cisplatin, doxorubicin, and paclitaxel exert significanteffects on the adhesion and migration of cancer cells, at sub-toxic concentrations. Importantly, these resultssuggest an important role for the aSMase/ceramide pathway in regulating these responses. These data andinsights lead us to the HYPOTHESIS that the aSMase/ceramide pathway is an important mediator of stressinducers, 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 asan upstream kinase in regulation of aSMase; b) the biochemical and cellular mechanisms by whichphosphorylation activates the enzyme; and c) the cellular compartment where aSMase is activated. 2) Todetermine 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 anddefining the role of this pathway in tumor metastasis/growth in vivo. 3) To determine the mechanisms bywhich the aSMase/ceramide pathway mediates cell stress responses. Understanding this pathway shouldhave great impact on the field of ceramide-mediated biology precisely by beginning to untangle thecomplexity of these pathways through provision of pathway-specific insight. Equally as important, definingupstream and downstream components of this pathway, which is activated by agents of significanttherapeutic value, may result in defining novel therapeutic targets in cancer therapy. Finally, there is thetantalizing possibility that the role of this pathway in inhibition of cell migration in response tochemotherapeutic agents may lead to a re-examination of therapeutically relevant actions of these agents byfocusing on their effects on migration and metastasis rather than on cytotoxicity or proliferation.
Showing the most recent 10 out of 215 publications
