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A peroxisome proliferator-activated
receptor-γ (PPARγ) agonist, troglitazone, facilitates
caspase-8 and -9 activities by increasing the enzymatic activity of
protein tyrosine phosphatase-1B on human glioma cells
Yasuharu Akasaki, Gentao Liu,
Harry H. Matundan, Hiushan Ng, Xiangpeng Yuan, Zhaohui Zeng, Keith L.
Black, and John S. Yu
Maxine Dunitz Neurosurgical
Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
Corresponding Author: akasaki@zj8.so-net.ne.jp .Submitted
on May 13, 2005. Accepted
on November 30, 2005
Despite dramatic advances in adjuvant
therapies, patients with malignant glioma face a bleak
prognosis.
Since 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 propose a novel mechanism of pro-apoptotic effect induced by
a pharmacological Peroxisome Proliferator-activated Receptor-gamma (PPARgamma)
agonist, Troglitazone, that facilitates caspase signaling in human
glioma cells.
Troglitazone activates Protein Tyrosine Phosphatase (PTP)-1B, which
subsequently reduces phospho-tyrosine-705 STAT3 (pY705-STAT3) via a
PPARgamma-independent pathway.
Reduction of pY705-STAT3 in glioma cells caused down-regulation of
FLICE-inhibitory protein (FLIP) and Bcl-2.
Furthermore, Troglitazone induced Serine-392-phosphorylation of p53
via a PPARgamma-dependent pathway and up-regulation of Bax in a
p53-wild-type glioma.
When given with TRAIL or caspase-dependent chemotherapeutic agents,
such as Etoposide and Pacritaxel, Troglitazone exhibited a synergistic
effect by facilitating caspase-8/9 activities.
A PPARgamma antagonist, GW9662, did not block this effect, although a
PTP inhibitor (PTPI) abrogated it.
Knockdown of STAT3 by STAT3-siRNA negated the inhibitory effect of
PTPI 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.
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