期刊
JOURNAL OF SURGICAL RESEARCH
卷 158, 期 1, 页码 15-19出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jss.2009.05.032
关键词
MG-132; proteasome inhibitor; carcinoid; glycogen synthase kinase-3 beta; ASCL1; apoptosis
类别
资金
- National Institutes of Health [R21 CA117117, R01 CA121115, CA109053, T32 CA090217]
- American College of Surgeons George H. A. Clowes Jr. Memorial Research Career Development Award
- Carcinoid Cancer Foundation
- Howard Hughes Medical Institute
- Society of Surgical Oncology Clinical Investigator Award
- NATIONAL CANCER INSTITUTE [R01CA121115, R01CA109053, T32CA090217, R21CA117117] Funding Source: NIH RePORTER
Background. Carcinoid cancers are the most common neuroendocrine (NE) tumors, and limited treatment options exist. The inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta. Materials and Methods. Human pulmonary (NCI-H727) and gastrointestinal (BON) carcinoid cells were treated with MG-132 (0-4 mu M). Cellular growth was measured by the 3-[4,5-dimethylthiazole-2-y1]-2,5 diphenyl tetrazolium bromide (MTT) assay. Levels of total and phosphorylated GSK-3 beta 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-3 beta 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. (C) 2010 Elsevier Inc. All rights reserved.
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