SB203580, a specific inhibitor of p38 phosphor-ylation, also attenuated TNF a induced cell death, thereby linking activation of p38 to apoptotic pathways in Schwann cells. P38 phosphorylation was also increased by LY294002, a specific PI3K inhibitor, suggesting convergence of these signaling pathways. Collectively, these data indicate that prosaptides regulate signaling pathways that antagonize pro-apoptotic signaling events. Supported by Myelos Corporation . Mayo Molecular Neuroscience Program, Rochester, MN 55905.
Sensory neuropathy is a debilitating side effect associated with a number of anti-cancer drugs.
The focus of the present study was to characterize the molecular elements mediating cell cycle re-entry and neuronal death. In suramin treated neuronal cultures, the lipid messenger ceramide was found to be a specific signaling element. Ceramide accumulation mediated activation and nuclear translocation of the transcription factor NF k B with subsequent cyclin D1 protein expression, a G1 phase specific protein. Specific inhibition of NF k B using a novel molecular decoy strategy resulted in increased cell viability accompanied by diminished caspase-3 activity. Inhibition of NFkB activity reduced cyclin D1 expression to control levels.