Unknown

Dataset Information

0

Glycogen synthase kinase-3? inhibition promotes lysosome-dependent degradation of c-FLIPL in hepatocellular carcinoma.


ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) 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-3? inhibition triggered ASK1-JNK-dependent apoptosis in human hepatocellular carcinoma (HCC) cells. However, the comprehensive picture of downstream GSK-3?-regulated pathways/functions remains elusive. In this study, we showed that GSK-3? was aberrantly activated in HCC. Pharmacological inhibition and genetic depletion of GSK-3? suppressed the growth and induced caspase-dependent apoptosis in HCC cells. In addition, GSK-3? 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-3? 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-3? promotes lysosome-dependent degradation of c-FLIPL. Our study shows that GSK-3? may become a promising therapeutic target for HCC.

SUBMITTER: Zhang N 

PROVIDER: S-EPMC5833564 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4805474 | biostudies-literature
| S-EPMC8202891 | biostudies-literature
| S-EPMC8138761 | biostudies-literature
| S-EPMC4144855 | biostudies-literature
| S-EPMC3116015 | biostudies-literature
| S-EPMC6677269 | biostudies-literature
| S-EPMC4449797 | biostudies-literature
| S-EPMC3503340 | biostudies-other
| S-EPMC1899930 | biostudies-literature
| S-EPMC3335080 | biostudies-literature