Suberoyl bis-hydroxamic acid activates Notch-1 signaling and induces apoptosis in medullary thyroid carcinoma cells. Oncologist 2008 Feb;13(2):98-104
Date
02/29/2008Pubmed ID
18305053DOI
10.1634/theoncologist.2007-0190Scopus ID
2-s2.0-40349091384 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
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.
Author List
Ning L, Greenblatt DY, Kunnimalaiyaan M, Chen HMESH terms used to index this publication - Major topics in bold
Antineoplastic AgentsApoptosis
Biomarkers, Tumor
Blotting, Western
Carcinoma, Medullary
Caspase 3
Cell Proliferation
Chromogranin A
Down-Regulation
Gene Expression Regulation, Neoplastic
Humans
Hydroxamic Acids
Poly(ADP-ribose) Polymerases
Receptor, Notch1
Signal Transduction
Thyroid Neoplasms
Tumor Cells, Cultured
