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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Cancer+Sci
2017 ; 108
(3
): 520-527
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WP1066 suppresses macrophage cell death induced by inflammasome agonists
independently of its inhibitory effect on STAT3
#MMPMID28035720
Honda S
; Sadatomi D
; Yamamura Y
; Nakashioya K
; Tanimura S
; Takeda K
Cancer Sci
2017[Mar]; 108
(3
): 520-527
PMID28035720
show ga
The compound WP1066 was originally synthesized by modifying the structure of
AG490, which inhibits the activation of signal transducer and activator of
transcription 3 (STAT3) by directly targeting Janus kinases (JAKs). WP1066
exhibits stronger anti-cancer activity than AG490 against malignant glioma and
other cancer cells and is regarded as a promising therapeutic agent. By screening
a small library of target-known compounds, we identified WP1066 as an inhibitor
of macrophage cell death induced by agonists of the NLRP3 inflammasome, an
intracellular protein complex required for the processing of the proinflammatory
cytokine interleukin (IL)-1?. WP1066 strongly inhibited cell death as well as
extracellular release of IL-1? induced by inflammasome agonists in mouse
peritoneal exudate cells and human leukemia monocytic THP-1 cells that were
differentiated into macrophagic cells by treatment with PMA. However,
inflammasome agonists did not increase STAT3 phosphorylation, and another JAK
inhibitor, ruxolitinib, did not inhibit cell death, although it strongly
inhibited basal STAT3 phosphorylation. Thus, WP1066 appears to suppress
macrophage cell death independently of its inhibitory effect on STAT3. In
contrast, WP1066 itself induced the death of undifferentiated THP-1 cells,
suggesting that WP1066 differentially modulates cell death in a context-dependent
manner. Consistent with previous findings, WP1066 induced the death of human
glioma A172 and T98G cells. However, neither ruxolitinib nor AG490, the former of
which completely suppressed STAT3 phosphorylation, induced the death of these
glioma cells. These results suggest that WP1066 targets cell death-modulating
molecules other than those involved in JAK-STAT3 signaling.