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

Abstract

There is growing interest in using peroxisome proliferator-activated receptor (PPAR) gamma agonists as chemotherapeutic agents in hematologic malignancies. PPARgamma agonists of diverse chemical structure induce apoptosis in several malignant B cell lines. However, PPARgamma agonists also induce apoptosis in normal B cells. One such agonist, GW7845, rapidly induces apoptosis in early B cells. Understanding the mechanisms of PPARgamma agonist-induced death is essential to minimizing loss of normal cells during chemotherapy. PPARgamma 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 NH(2)-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.

Rosiglitazone, an Agonist of PPARγ, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2

“…PPAR γ ligands have been shown to induce the activation of p38 MAPK in different cell systems [16, 17]. In line with this, we showed that rosiglitazone increased the phosphorylation of p38 MAPK in NSCLC cells.…”

“…PPAR γ ligands have been shown to induce the activation of p38 MAPK in different cell systems [16, 17]. Activation of p38 mitogen-activated protein kinase (MAPK) and its downstream kinase MK2 have been associated with the phosphorylation of TSC2 [18].…”

The contribution of c-Jun N-terminal kinase activation and subsequent Bcl-2 phosphorylation to apoptosis induction in human B-cells is dependent on the mode of action of specific stresses

“…SP6 is a specific and potent catalytic inhibitor of JNK that has been widely employed to determine the contribution of the JNK pathway to apoptosis induced by numerous agents in a variety of cell types. It has been particularly useful in elucidating the role of the JNK pathway in the induction of apoptosis in primary cell cultures and established cell lines of B-lymphoid lineage cells (Bloom et al, 2006;Schlezinger et al, 2006). Both arsenite and vincristine induced apoptosis in EW36 B-cells in a concentration dependent manner (Figure 2; A and B, respectively).…”

Tetramethylpyrazine attenuates PPAR-γ antagonist-deteriorated oxazolone-induced colitis in mice

“…MAPK cascade transducer signals from the cell surface change the gene expression that controls diverse functions such as the inflammatory response of epithelial cells (38), proliferation, differentiation, transformation and apoptosis (39). In particular, p38 MAPK is a key modulator of several target genes that ultimately control infiltration of monocytic cells, acute intestinal inflammation and intestinal electrolyte and water secretion, and in response to a variety of stimuli regulates cytokine production (40).…”