MG-132 inhibits carcinoid growth and alters the neuroendocrine phenotype.
BACKGROUND
Carcinoid cancers are the most common neuroendocrine (NE) tumors, and limited treatment options exist. The inhibition of glycogen synthase kinase-3beta (GSK-3beta) has been shown to be a potential therapeutic target for the treatment of carcinoid disease. In this study, we investigate the ability of MG-132, a proteasome inhibitor, to inhibit carcinoid growth, the neuroendocrine phenotype, and its association with GSK-3beta.


METHODS
Human pulmonary (NCI-H727) and gastrointestinal (BON) carcinoid cells were treated with MG-132 (0-4microM). Cellular growth was measured by the 3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Levels of total and phosphorylated GSK-3beta and the NE markers chromogranin A (CgA), Achaete-Scute complex-like 1 (ASCL1), as well as the apoptotic markers poly (ADP-ribose), polymerase (PARP), and cleaved caspase-3 were determined by Western blot.


RESULTS
Treating carcinoid cells with MG-132 resulted in growth inhibition, a dose-dependent inhibition of CgA and ASCL1, as well as an increase in the levels of cleaved PARP and cleaved caspase-3. Additionally, an increase in the level of phosphorylated GSK-3beta was observed.


CONCLUSIONS
MG-132 inhibits cellular growth and the neuroendocrine phenotype. This proteasome inhibitor warrants further preclinical investigation as a possible therapeutic strategy for intractable carcinoid disease.
Chen
Jui-yu
JY
Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA. chen@surgery.wisc.edu
Cook
Mackenzie R
MR
Pinchot
Scott N
SN
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000032:analysis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D009490:Neurosecretory Systems / Q000187:drug effects*; D010641:Phenotype; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D053379:Chromogranin A; D015853:Cysteine Proteinase Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007976:Leupeptins; C065500:ASCL1 protein, human; C000605506:GSK3B protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde