MG-132 Inhibits Carcinoid Growth and Alters the Neuroendocrine Phenotype

Chen, Jui-yu; Cook, Mackenzie R.; Pinchot, Scott N.; Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1016/j.jss.2009.05.032

« Previous Next »Journal of Surgical Research
Volume 158, Issue 1 , Pages 15-19, January 2010

MG-132 Inhibits Carcinoid Growth and Alters the Neuroendocrine Phenotype

Jui-yu Chen, M.D.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin
- Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
Mackenzie R. Cook, B.A.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin
Scott N. Pinchot, M.D.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin
Muthusamy Kunnimalaiyaan, Ph.D.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin
Herbert Chen, M.D., F.A.C.S.
- Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wisconsin
- To whom correspondence and reprint requests should be addressed at Department of Surgery, University of Wisconsin, H4/722 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.

Received 13 January 2009 published online 22 June 2009.

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.

Key Words: MG-132, proteasome inhibitor, carcinoid, glycogen synthase kinase-3β, ASCL1, apoptosis