Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells. Surgery 2008 Dec;144(6):956-61; discussion 961-2
Date
12/02/2008Pubmed ID
19041003Pubmed Central ID
PMC2638099DOI
10.1016/j.surg.2008.08.027Scopus ID
2-s2.0-48749119660 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
BACKGROUND: The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have been demonstrated recently to be strong Notch-1 activators. Upregulation of the Notch-1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) neoplasms. We hypothesized that HDAC inhibition would be an effective strategy to activate the Notch-1 pathway and inhibit growth and hormonal secretion in pheochromocytoma cells.
METHODS: Pheochromocytoma PC-12 cells were treated with up to 8 mmol/L VPA or 40 micromol/L SBHA for 2 days. NE tumor markers achaete-scute complex-like 1 (ASCL1) and chromogranin A (CgA) were measured by Western analysis after treatment. Growth was assessed by a cellular proliferation assay; Western analysis was used to determine the mechanism of growth regulation.
RESULTS: HDAC inhibitor treatment caused a dose-dependent decrease in ASCL1 and CgA while increasing the amount of active Notch-1 protein; with a 6-day treatment, dose-dependent growth inhibition and cleavage of the apoptotic markers caspase-3 and poly-ADP ribose phosphate was observed.
CONCLUSION: VPA and SBHA upregulate Notch-1 effectively, suppress NE tumor markers, and decrease growth via apoptosis of pheochromocytoma cells in vitro. Activation of the Notch-1 signaling pathway with HDAC inhibitors may represent a new strategy for treating pheochromocytomas.
Author List
Adler JT, Hottinger DG, Kunnimalaiyaan M, Chen HMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Proliferation
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Hydroxamic Acids
PC12 Cells
Rats
Receptor, Notch1
Up-Regulation
Valproic Acid
