AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Transl Res 2009;1(4):358-366

Original Article
Down-regulation of Notch1 signaling inhibits tumor growth in human
hepatocellular carcinoma

Li Ning, Lucy Wentworth, Herbert Chen, Sharon M. Weber

Department of Surgery, University of Wisconsin School of Medicine and Public Health, and the University of
Wisconsin Paul P. Carbone Comprehensive Cancer Center, William S. Middleton Veteran’s Hospital, Madison,
Wisconsin, USA

Received June 20, 2009; accepted July, 2, 2009; available online July 10, 2009

Abstract: In some human cancers, the Notch1 receptor and signaling pathway is upregulated, which increases
the oncogenic potential of the cell through prevention of differentiation and inhibition of apoptosis. We sought to
evaluate the role of Notch1 in hepatocellular cancer (HCC), and evaluate the therapeutic efficacy of curcumin, a
known Notch1 inhibitor. Human liver tumors were compared to normal liver to evaluate for Notch1 and Notch1
Intracellular Domain (NICD). Three human HCC cell lines were exposed to curcumin and evaluated for
downstream effectors by Western blot. In addition, standard MTT assays were performed to assess the effect of
curcumin in vitro. Finally, a nude mouse xenograft model was utilized to assess the response to curcumin in vivo.
High levels of NICD were present in the majority of human HCC samples and all three HCC cell lines. Treatment
with curcumin led to a dose-dependent decrease in the expression of NICD associated with the induction of
cleaved poly ADP-ribose polymerase (PARP), the degradation of cyclin D1 and increase in cyclin-dependent
kinase p21. Curcumin inhibited HCC cell proliferation in vitro. Importantly, transfection of Notch1 small-interfering
RNA (siRNA) into HCC cells resulted in cell growth inhibition and apoptosis, recapitulating the effects of
curcumin. Finally, treatment with curcumin resulted in a 40% decrease in tumor growth in vivo. These results
suggest for the first time that down-regulation of Notch1 signaling with curcumin is an attractive new therapeutic
strategy for the treatment of patients with HCC. (AJTR906002).

Key words: Hepatocellular carcinoma, curcumin, Notch1, apoptosis

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Address all correspondence to:
Sharon Weber, MD
H4/752 Clinical Science Center,
600 Highland Avenue
Madison, Wisconsin 53792-7375
Tel: (608) 263-1387
Email:
webers@surgery.wisc.edu.