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Endocrinology

Suberoyl Bis-Hydroxamic Acid Activates Notch-1 Signaling and Induces Apoptosis in Medullary Thyroid Carcinoma Cells

Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA

Key Words. Suberoyl bis-hydroxamic acid • SBHA • Medullary thyroid carcinoma • Neuroendocrine tumors • Notch-1 • Achaete-scute complex-like 1 • ASCL-1 • Chromogranin A • Apoptosis

Correspondence: Herbert Chen, M.D., H4/750 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792-7375, USA. Telephone: 608-263-1387; Fax: 608-263-7652; e-mail: chen{at}surgery.wisc.edu; or Muthusamy Kunnimalaiyaan, K4/638 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792-7375, USA. Telephone: 608-265-3749; Fax: 608-263-8613; e-mail: kunni{at}surgery.wisc.edu

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

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.

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