A Peroxisome Proliferator-activated Receptor-γ Agonist, Troglitazone, Facilitates Caspase-8 and -9 Activities by Increasing the Enzymatic Activity of Protein-tyrosine Phosphatase-1B on Human Glioma Cells

Abstract

Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Because many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here we proposed a novel mechanism of proapoptotic effect induced by a pharmacological peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist, troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates protein-tyrosine phosphatase (PTP)-1B, which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPAR␥-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLIP (FADD-like IL-1␤-converting enzyme-inhibitory protein) and Bcl-2. Furthermore, troglitazone induced Ser-392 phosphorylation of p53 via a PPAR␥-dependent pathway and up-regulation of Bax in a p53 wild-type glioma. When given with tumor necrosis factor-related apoptosisinducing ligand or caspase-dependent chemotherapeutic agents, such as etoposide and paclitaxel, troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPAR␥ antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it. Knockdown of STAT3 by STAT3-small interfering RNA negated the inhibitory effect of PTP inhibitor on troglitazone, indicating that troglitazone uses a STAT3 inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells and that PTP1B plays a critical role in the down-regulation of activated STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.

Rosiglitazone promotes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

“…The ability of PPARγ agonists to enhance apoptosis induced by TRAIL has been shown in several other types of cancer cell lines [37,[40][41][42][43]. Lu et al [40] reported that PPARγ agonists of the thiazolidinedione class sensitize breast cancer cells to TRAIL by reduction of cyclin D3 through decreasing cyclin D3 mRNA levels and inducing cyclin D3 proteasomal degradation.…”

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

“…Troglitazone (TG) is an activator of protein tyrosine phosphatase 1B (PTP1B); it reduces PY705-STAT3 and promotes apoptosis in human primary gliomas (34). We tested whether TG stimulated p53 expression and apoptosis in CLL.…”

Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of FcγR Phagocytosis by Prostaglandin E2 in Alveolar Macrophages

“…The PTEN inhibitor dipotassium bisperoxo(pyridine-2-carboxyl)oxovanadate (bpV(pic)) (28) and the Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) inhibitor ␣-bromo-4-(carboxymethoxy)-acetophenone (SHPI; Ref. 29) were purchased from Calbiochem. Lipofectin reagent was obtained from Molecular Probes.…”