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

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  • Li Ning
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA
  • David Yu Greenblatt
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA
  • Muthusamy Kunnimalaiyaan
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA
  • Herbert Chen
    Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA

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<jats:title>Abstract</jats:title><jats:p>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-XL 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.</jats:p>

Journal

  • The Oncologist

    The Oncologist 13 (2), 98-104, 2008-02-01

    Oxford University Press (OUP)

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