The
ubiquitin-
proteasome pathway is responsible for regulating
cell cycle proteins,
tumor-suppressor molecules, oncogenes,
transcription factors, and pro- and
anti-apoptotic proteins. The aim of this study is to evaluate the effects of
proteasome inhibitors on human
hepatocellular carcinoma (HCC) cells. HCC cells SK-Hep1, HLE and HepG2 were treated with the
proteasome inhibitors MG132 and
MG115. Our data showed that both inhibitors induce apoptosis in the three cell types tested in a dose-dependent manner. Moreover, subtoxic levels of
MG132 and
MG115 sensitized HCC cells to TRAIL-induced apoptosis. To investigate the mechanism of increased TRAIL sensitivity in HCC cells, we first examined surface expression of TRAIL and its receptors.
MG132 upregulated TRAIL and its receptors (TRAIL-R1 and -R2) in SK-Hep1 and HLE, whereas
MG115 upregulated them in SK-Hep1.
MG132 downregulated expression of
X-linked inhibitor of apoptosis protein (XIAP) in SK-Hep1 and HLE, and of
survivin in all three cell-types.
MG115 downregulated expression of XIAP in SK-Hep1, and
survivin in SK-Hep1 and HepG2. Furthermore,
MG132 downregulated phospho-AKT and its downstream target phospho-BAD, indicating that
MG132 activated the mitochondrial apoptosis pathway by inhibiting phosphorylation of AKT and BAD. In conclusion,
proteasome inhibitors induced apoptosis and augmented TRAIL sensitivity via both the IAP family and AKT pathways. Thus, combining
proteasome inhibitors with a TRAIL agonist may provide a new therapeutic strategy for HCC.