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Carcinogenesis Advance Access published online on May 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi133
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Published by Oxford University Press 2005
Received March 29, 2005
Revised May 10, 2005
Accepted May 13, 2005

CANCER BIOLOGY

Justicidin A decreases the level of cytosolic Ku70 leading to apoptosis in human colorectal cancer cells

Jenq-Chang Lee 1, Chao-Hung Lee 2, Chun-Li Su 3, Chung-Wei Huang 4, Hsiao-Sheng Liu 4, Chun-Nan Lin 5, and Shen-Jeu Won 4*

1 Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
3 Department of Nursing, Chang Jung Christian University, Tainan, Taiwan
4 Department of Microbiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5 School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan

* To whom correspondence should be addressed.
Shen-Jeu Won, E-mail: a725{at}mail.ncku.edu.tw


  Abstract

The natural product justicidin A, an arylnaphthalide lignan isolated from Justicia procumbens, significantly inhibited the growth of human colorectal cancer cells HT-29 and HCT 116 at day 6 post-treatment. Further study revealed that justicidin A-treated HT-29 and HCT 116 colorectal cancer cells died of apoptosis. Justicidin A treatment caused DNA fragmentation and an increase in phosphatidylserine exposure of the cells. The number of cells in the sub-G1 phase was also increased upon justicidin A treatment. Caspase-9 but not caspase-8 was activated, suggesting that justicidin A treatment damaged mitochondria. The mitochondrial membrane potential ({Delta}{psi}m) was altered and cytochrome c and Smac were released from mitochondria to the cytoplasm upon justicidin A treatment. The level of Ku70 in the cytoplasm was decreased, but that of Bax in mitochondria was increased by justicidin A. Since Ku70 normally binds and sequesters Bax, these results suggest that justicidin A decreases the level of Ku70 leading to translocation of Bax from the cytosol to mitochondria to induce apoptosis. Oral administration of justicidin A was shown to suppress the growth of HT-29 cells transplanted into NOD-SCID mice, suggesting chemotherapeutic potential of justicidin A on colorectal cancer cells.

Keywords: justicidin A; Ku70; mitochondria; caspases; apoptosis.
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