TY - JOUR
T1 - MG-132 Inhibits Carcinoid Growth and Alters the Neuroendocrine Phenotype
AU - Chen, Jui yu
AU - Cook, Mackenzie R.
AU - Pinchot, Scott N.
AU - Kunnimalaiyaan, Muthusamy
AU - Chen, Herbert
N1 - Funding Information:
The authors acknowledge support from the National Institutes of Health Grants R21 CA117117, R01 CA121115, and CA109053 (HC); American College of Surgeons George H. A. Clowes Jr. Memorial Research Career Development Award (HC); Carcinoid Cancer Foundation Research Grant (HC), NIH T32 CA090217 (SNP), Howard Hughes Medical Institute (MRC), and the Society of Surgical Oncology Clinical Investigator Award (HC).
PY - 2010/1
Y1 - 2010/1
N2 - Background: Carcinoid cancers are the most common neuroendocrine (NE) tumors, and limited treatment options exist. The inhibition of glycogen synthase kinase-3β (GSK-3β) 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-3β. Materials and Methods: Human pulmonary (NCI-H727) and gastrointestinal (BON) carcinoid cells were treated with MG-132 (0-4μM). 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-3β 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-3β was observed. Conclusion: 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.
AB - Background: Carcinoid cancers are the most common neuroendocrine (NE) tumors, and limited treatment options exist. The inhibition of glycogen synthase kinase-3β (GSK-3β) 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-3β. Materials and Methods: Human pulmonary (NCI-H727) and gastrointestinal (BON) carcinoid cells were treated with MG-132 (0-4μM). 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-3β 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-3β was observed. Conclusion: 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.
KW - ASCL1
KW - MG-132
KW - apoptosis
KW - carcinoid
KW - glycogen synthase kinase-3β
KW - proteasome inhibitor
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U2 - 10.1016/j.jss.2009.05.032
DO - 10.1016/j.jss.2009.05.032
M3 - Article
C2 - 19765735
AN - SCOPUS:71649102450
SN - 0022-4804
VL - 158
SP - 15
EP - 19
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -