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

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