Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells

Academic Article

Abstract

  • 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 μmol/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. © 2008 Mosby, Inc. All rights reserved.
  • Published In

  • Surgery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Adler JT; Hottinger DG; Kunnimalaiyaan M; Chen H
  • Start Page

  • 956
  • End Page

  • 962
  • Volume

  • 144
  • Issue

  • 6