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First published on June 24, 2008; DOI: 10.1124/mol.107.044800
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Received for publication January 3, 2008.
Revised June 23, 2008.
Accepted for publication June 23, 2008.

The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma (HCC) cells therapy

Yi-Lin Chen 1, Min-Hui Jian 1, Chai-Ching Lin 2, Jung-Cheng Kang 3, Shee-Ping Chen 4, Po-Cheng Lin 5, Putzer-Joseph Hung 6, Jen-Ren Chen 7, Wen-Liang Chang 8, Shinn-Zong Lin 9, Horng-Jyh Harn 10*

1 Graduate Institute of Biotechnology, National Ilan University, Ilan, Taiwan. 2 Department of Applied Animal Science, National Ilan University, Ilan, Taiwan. 3 Division of Colon and Rectum Surgery, Buddish Tzu-Chi General University and Hospital, Hualien. 4 Institute of Medical Sciences, Buddhist Tzu-Chi University, Hualien, Taiwan. 5 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien. 6 Department of Biochemistry, Brown University Providence, RI 02912, USA 7 Division of Biotechnology, Agricultural Research Institute, Wufeng, Taichung, Taiwan. 8 School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. 9 Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. 10 Department of Pathology, China Medical University and Hospital, Taichung, Taiwan.

* Address correspondence to: E-mail: duke_harn{at}yahoo.com.tw

Abstract

N-butylidenephthalide, isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either n-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77 were evaluated as well as the effect of n-butylidenephthalide in an in vivo xenograft model. N-butylidenephthalide caused growth inhibition of both the cell lines at 25 µg/ml. Further, n-butylidenephthalide-induced apoptosis appears to be related to Nur77 translocation from nucleus to cytosol, which lead to cytochrome c release and caspase-3-dependent apoptosis. N-butylidenephthalide-related tumor apoptosis was associated with PI3K/AKT/GSK3{beta} rather than the MAPK or PKC pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phospho-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild type cAMP-responsive element binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of n-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-butylidenephthalide-induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of HCCs.


Key words: Promoter analysis, Immunocytochemistry, Regulation of gene expression, Apoptosis, RNA/siRNA




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