Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor.
OBJECTIVE
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer deaths worldwide. Inhibitors of cholesterol biosynthesis ('statins') have been proposed as promising adjunctive anticancer agents to treat HCC, but their mode of action is yet poorly characterized. We additionally investigated the potential benefit of a combination of peripheral benzodiazepine receptor (PBR) ligands and statins.


METHODS
We analyzed the growth inhibitory effects of PBR ligands, statins, and their combination in two human HCC cell lines. Moreover, we investigated the regulation of cellular cholesterol levels and the expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoAR), the target of statins.


RESULTS
Statins inhibited the proliferation of HCC cells by inducing apoptosis and G1/S cell cycle arrest. Statin-induced apoptosis was characterized by a breakdown of the mitochondrial membrane potential, caspase activation and nuclear degradation. Furthermore, activation of ERK1/2 was downregulated while p38MAPK was activated. Synergistic growth inhibition was obtained by the combination of the PBR ligand FGIN-1-27 with statins. PBR ligands induced a decrease of HMG-CoAR expression. This downregulation may be responsible for the enhanced sensitivity of HCC cells to statins.


CONCLUSIONS
Our data shed light on the signaling cascades mediating statin-induced growth inhibition of HCC cells. Moreover, PBR ligands sensitized HCC cells to statins, suggesting a new strategy to treat HCC.
Sutter
Andreas P
AP
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Berlin, Germany.
Maaser
Kerstin
K
Höpfner
Michael
M
Huether
Alexander
A
Schuppan
Detlef
D
Scherübl
Hans
H
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008024:Ligands; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D011963:Receptors, GABA-A; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases