Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells
Journal
Cancer Research
Journal Volume
68
Journal Issue
16
Pages
6698-6707
Date Issued
2008
Author(s)
Abstract
Bortezomib, a proteasome inhibitor, has been clinically approved for the treatment of myeloma and lymphoma. Here, we report a differential effect of bortezomib on apoptosis in four hepatocellular carcinoma (HCC) cell lines and identify the major molecular event that determines sensitivity. Although bortezomib inhibited proteasome activity to a similar extent in all HCC cell lines, it showed differential effects on their viability: Huh-7 (IC50 196 nmol/L), Sk-Hepl (IC50 180 nmol/L), Hep3B (IC50 112 nmol/L), and resistant PLC5 (IC50 >1,000 nmol/L). Bortezomib caused cycel cycle arrest at G2-M phase in all HCC cells tested whereas apoptotic induction was found only in sensitive cells but not in PLC5 cells. No significant bortezomib-induced NF-κB changes were noted in Huh-7 and PLC5. Bortezomib down-regulated phospho-Akt (P-Akt) in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations of P-Akt were found in PLC5. Down-regulation of Aktl by small interference RNA overcame the apoptotic resistance to bortezomib in PLC5 cells, but a constitutively activated Akt1 protected Huh-7 cells from bortezomib-induced apoptosis. Furthermore, bortezomib showed suppression of tumor growth with downregulation of P-Akt in Huh-7 tumors but not in PLC5 tumors. Down-regulation of P-Akt represents a major molecular event of bortezomib-induced apoptosis in HCC cell lines and may be a biomarker for predicting clinical response to HCC treatment. Targeting Akt signaling overcomes drug resistance to bortezomib in HCC cells, which provides a new approach ? 2008 American Association for Cancer Research.
SDGs
Other Subjects
2 morpholino 8 phenylchromone; biological marker; bortezomib; immunoglobulin enhancer binding protein; proteasome; protein kinase B; rapamycin; small interfering RNA; antineoplastic agent; boronic acid derivative; bortezomib; pyrazine derivative; animal experiment; animal model; animal tissue; apoptosis; article; cancer cell culture; cancer inhibition; cell cycle arrest; cell cycle G2 phase; cell cycle M phase; cell viability; controlled study; dose response; down regulation; enzyme activity; human; human cell; IC 50; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein targeting; sensitivity analysis; signal transduction; animal; cell culture; cell cycle; drug antagonism; drug effect; drug screening; flow cytometry; genetics; liver cell carcinoma; liver tumor; metabolism; nude mouse; pathology; Western blotting; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Boronic Acids; Carcinoma, Hepatocellular; Cell Cycle; Down-Regulation; Flow Cytometry; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; NF-kappa B; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-akt; Pyrazines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Type
journal article