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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related death worldwide
All the cell lines with elevated Glycogen synthase kinase-3β (GSK-3β) expression showed higher levels of phosphorylation of glycogen synthase (p-GS), a primary GSK-3β substrate, as compared with normal HL7702, suggesting that GSK-3β is active in HCC cells (Fig. 1a, middle panel)
IB analysis revealed that increased protein expression level of GSK-3β and p-GS in tumor tissues compared with their normal counterparts (Fig. 1d)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related death worldwide. More than 600,000 deaths are attributed to HCC each year[1]. The short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis remains unsatisfactory, as indicated by the low overall survival of 22–35% at 10 years after. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that exists as two highly similar mammalian isoforms, GSK-3α, and GSK-3β5. The roles of GSK3β in cancer and tumor progression remain controversial[8,9]. Several studies suggested a possible role of GSK-3β as a tumor suppressor gene in HCC10–12, and loss of GSK-3β expression and/or inhibition
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