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2016 ; 7
(41
): 66892-66905
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Modulation of glycogen synthase kinase-3? following TRAIL combinatorial treatment
in cancer cells
#MMPMID27602497
Santha S
; Davaakhuu G
; Basu A
; Ke R
; Das S
; Rana A
; Rana B
Oncotarget
2016[Oct]; 7
(41
): 66892-66905
PMID27602497
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Glycogen Synthase Kinase-3? (GSK3?) is a serine/threonine kinase, known to
regulate various cellular processes including proliferation, differentiation,
survival, apoptosis as well as TRAIL-resistance. Thus pathways that can modulate
GSK3? axis are important targets for cancer drug development. Our earlier studies
have shown that combinatorial treatment with Troglitazone (TZD) and TRAIL can
induce apoptosis in TRAIL-resistant cancer cells. The current studies were
undertaken to investigate whether GSK3? pathway was modulated during this
apoptosis. Our results indicated an increase in inhibitory GSK3?Ser9
phosphorylation during apoptosis, mediated via AKT. At a later time, however, TZD
alone and TRAIL-TZD combination produced a dramatic reduction of GSK3?
expression, which was abolished by cycloheximide. Luciferase assays with
GSK3?-luc promoter reporter showed that TZD can effectively antagonize GSK3?
promoter activity. Since TZD is a ligand for transcription factor PPAR? and can
activate AMPK, we determined their roles on antagonism of GSK3?. Knockdown of
PPAR? was unable to restore GSK3? expression or antagonize GSK3?Ser9
phosphorylation. Although pretreatment with Compound C (pharmacological inhibitor
of AMPK) partially rescued GSK3? expression, knockdown of AMPK?1 or ?2 alone or
in combination were ineffective. These studies suggested a novel
PPAR?-AMPK-independent mechanism of targeting GSK3? by TZD, elucidation of which
might provide newer insights to improve our understanding of TRAIL-resistance.
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