Suberoyl bis-hydroxamic acid activates Notch-1 signaling and induces apoptosis in medullary thyroid carcinoma cells.

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine (NE) malignancy that frequently metastasizes and has limited treatments. We recently reported that ectopic expression of Notch-1 in human MTC cells suppresses growth. The objective of this study was to evaluate the ability of suberoyl bis-hydroxamic acid (SBHA) to modulate Notch-1 signaling in MTC cells. At baseline, no active Notch-1 protein was present in MTC cells. Treatment with SBHA resulted in a dose-dependent induction of the Notch-1 intracellular domain, the active form of the protein. Furthermore, with Notch-1 activation there was a concomitant decrease in achaete-scute complex-like 1 (ASCL-1), a downstream target of Notch-1 signaling, as well as the NE tumor marker chromogranin A (CgA). Transfection of Notch-1 small-interfering RNA into MTC cells blocked the effects of SBHA on Notch-1 activation, ASCL-1, and CgA. Importantly, SBHA treatment resulted in a dose-dependent decrease in cell viability. Treated cells had an increase in protein levels of cleaved caspase-3 and poly ADP-ribose polymerase, and changes in the expression of apoptotic mediators including Bcl-X(L) and Bad, indicating that the growth inhibition was a result of apoptosis. These results demonstrate that SBHA activates Notch-1 signaling, which is associated with the antiproliferative and apoptotic effects in MTC cells. Therefore, Notch-1 activation with SBHA is an attractive new strategy for the treatment of patients with MTC.

• Authors: Li Ning, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen
• Journal: The oncologist (Oncologist) Vol. 13 Issue 2 Pg. 98-104 (Feb 2008) ISSN: 1083-7159 [Print] England
• PMID: 18305053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Chromogranin A
• Hydroxamic Acids
• NOTCH1 protein, human
• Receptor, Notch1
• suberoyl bis-hydroxamic acid
• Poly(ADP-ribose) Polymerases
• Caspase 3

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Carcinoma, Medullary (drug therapy, metabolism, physiopathology)
• Caspase 3 (metabolism)
• Cell Proliferation (drug effects)
• Chromogranin A (metabolism)
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Hydroxamic Acids (pharmacology)
• Poly(ADP-ribose) Polymerases (drug effects)
• Receptor, Notch1 (drug effects, metabolism)
• Signal Transduction (drug effects)
• Thyroid Neoplasms (drug therapy, metabolism, physiopathology)
• Tumor Cells, Cultured