Suberoyl bis-hydroxamic acid activates Notch-1 signaling and induces apoptosis in medullary thyroid carcinoma cells.
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.
Ning
Li
L
Department of Surgery, University of Wisconsin, Wisconsin, USA.
Greenblatt
David Yu
DY
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053379:Chromogranin A; D006877:Hydroxamic Acids; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C528828:suberoyl bis-hydroxamic acid; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3