Abstract
Glycogen Synthase Kinase-3β (GSK3β) 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 GSK3β 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 GSK3β pathway was modulated during this apoptosis. Our results indicated an increase in inhibitory GSK3βSer9 phosphorylation during apoptosis, mediated via AKT. At a later time, however, TZD alone and TRAIL-TZD combination produced a dramatic reduction of GSK3β expression, which was abolished by cycloheximide. Luciferase assays with GSK3β-luc promoter reporter showed that TZD can effectively antagonize GSK3β promoter activity. Since TZD is a ligand for transcription factor PPARγ and can activate AMPK, we determined their roles on antagonism of GSK3β. Knockdown of PPARγ was unable to restore GSK3β expression or antagonize GSK3βSer9 phosphorylation. Although pretreatment with Compound C (pharmacological inhibitor of AMPK) partially rescued GSK3β expression, knockdown of AMPKα1 or α2 alone or in combination were ineffective. These studies suggested a novel PPARγ-AMPK-independent mechanism of targeting GSK3β by TZD, elucidation of which might provide newer insights to improve our understanding of TRAIL-resistance.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that has been implicated in regulating several fundamental processes including cell proliferation, differentiation, metabolism, survival and apoptosis [1], as well as various pathological conditions such as diabetes, oncogenesis and neurological diseases [2]
Since TZD is a ligand for transcription factor Peroxisome Proliferator-activated Receptor gamma (PPARγ) and can activate AMP-activated protein kinase (AMPK), we determined their roles on antagonism of Glycogen Synthase Kinase-3β (GSK3β)
Our results indicate that in Tumor Necrosis Factor-related Apoptosisinducing Ligand (TRAIL)-resistant prostate cancer and hepatocellular carcinoma (HCC) cells, TRAIL and TZD treatment resulted in an induction of GSK3βSer9 phosphorylation at an earlier stage during apoptosis
Summary
Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that has been implicated in regulating several fundamental processes including cell proliferation, differentiation, metabolism, survival and apoptosis [1], as well as various pathological conditions such as diabetes, oncogenesis and neurological diseases [2]. GSK3 derived its name from its phosphorylation activity toward glycogen synthase, linking it to glycogen metabolism. GSK3 is known to phosphorylate and regulate the activities of more than 40 proteins, many of which are transcription factors [5]. This indicates the potential contribution of this enzyme in regulating a variety of cellular functions. The major inhibitory phosphorylation is on Ser of GSK3β and Ser of GSK3α [8, 9] and can be phosphorylated by multiple upstream kinases including AKT [10]
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