Activation of Multiple Mitogen-Activated Protein Kinases in Pro/Pre–B Cells by GW7845, a Peroxisome Proliferator–Activated Receptor γ Agonist, and Their Contribution to GW7845-Induced Apoptosis

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Abstract
There is growing interest in using peroxisome proliferator–activated receptor (PPAR) γ agonists as chemotherapeutic agents in hematologic malignancies. PPARγ agonists of diverse chemical structure induce apoptosis in several malignant B cell lines. However, PPARγ agonists also induce apoptosis in normal B cells. One such agonist, GW7845, rapidly induces apoptosis in early B cells. Understanding the mechanisms of PPARγ agonist–induced death is essential to minimizing loss of normal cells during chemotherapy. PPARγ agonists influence mitogen-activated protein kinase (MAPK) cascades in other systems, and MAPKs can be associated with apoptosis. Therefore, we investigated the activation of MAPKs in primary pro–B cells and cultured pro/pre–B cells and their role in GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre–B-cell line with GW7845 transiently induced the phosphorylation of extracellular signal–related protein kinase (ERK) 1/2, but strongly and persistently induced the activation of p38 MAPK and c-Jun NH2-terminal kinase (JNK). In primary pro–B-cells, p38 MAPK and JNK were activated following treatment with GW7845. Phosphorylation of activating transcription factor-2 (ATF-2) was induced strongly in both B-cell types. In pro/pre–B cells, pretreatment with the p38 MAPK/JNK inhibitor PD169316 potently suppressed multiple facets of GW7845-induced apoptosis signaling. However, when a series of p38 MAPK and JNK inhibitors were used, only SB202190, also a dual inhibitor, completely suppressed GW7845-induced apoptosis. Inhibitors specific for p38 MAPK and JNK were only partially effective, suggesting that suppression of a single MAPK is not sufficient to inhibit death. The results support the hypothesis that GW7845 initiates an apoptotic pathway in early B cells through the activation of a kinase cascade that includes at least p38 MAPK and JNK.

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