Figure 9

Agents that restore GC-sensitivity to CEM-C1-15 cells converge on the GR and MAPK pathways. Dex-resistant CEM-C1-15 cells in their natural state harbor high levels of pro-survival, anti-apoptotic active JNK (green symbol) and low levels of active ERK which is Dex-inducible (blue symbol). The cells also contain GR (pink symbol). The sequence on the left side shows the result in CEM cells which resist Dex-dependent apoptosis. In this case, added Dex mediates a weak increase in GR phospho-Ser 211 as well as GRE reporter driven activity, but no increase in GR protein levels, and the cells remain resistant. The sequence on the right depicts the results when CEM-C1-15 cells are treated with combinations of Dex and MAPK inhibitors, FSK, or rapamycin. These treated cells convert to a GC-sensitive phenotype. All treatments converge at inhibition of the JNK MAPK pathway. Upon restoration of the Dex-sensitive phenotype, a robust increase in GR phospho-Ser 211, GR protein, and transcriptional activity is observed. These effects culminate in an apoptotic response.