Abstract
Glycogen synthase kinase-3β (GSK-3β) is a ubiquitously expressed serine/threonine kinase involved in a variety of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK-3β inhibition triggered ASK1-JNK-dependent apoptosis in human hepatocellular carcinoma (HCC) cells. However, the comprehensive picture of downstream GSK-3β-regulated pathways/functions remains elusive. In this study, we showed that GSK-3β was aberrantly activated in HCC. Pharmacological inhibition and genetic depletion of GSK-3β suppressed the growth and induced caspase-dependent apoptosis in HCC cells. In addition, GSK-3β inhibition-induced apoptosis through downregulation of c-FLIPL in HCC, which was caused by biogenesis of functional lysosomes and subsequently c-FLIPL translocated to lysosome for degradation. This induction of the lysosome-dependent c-FLIPL degradation was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Moreover, GSK-3β inhibition-induced TFEB translocation acts through activation of AMPK and subsequently suppression of mTOR activity. Thus our findings reveal a novel mechanism by which inhibition of GSK-3β promotes lysosome-dependent degradation of c-FLIPL. Our study shows that GSK-3β may become a promising therapeutic target for HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Amino Acid Sequence
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Apoptosis / drug effects
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Apoptosis / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cytoskeletal Proteins / antagonists & inhibitors
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Cytoskeletal Proteins / genetics*
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Cytoskeletal Proteins / metabolism
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Cytosol / drug effects
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Cytosol / metabolism
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Gene Expression Regulation
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Hep G2 Cells
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Humans
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Lysosomes / drug effects
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Lysosomes / metabolism*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Protein Stability
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Proteolysis
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Thiazoles / pharmacology
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Urea / analogs & derivatives
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Urea / pharmacology
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Cytoskeletal Proteins
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NIN protein, human
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Nuclear Proteins
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RNA, Small Interfering
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Thiazoles
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N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
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Urea
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MTOR protein, human
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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CASP3 protein, human
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Caspase 3