Journal Article

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

Jenq-Chang Lee, Chao-Hung Lee, Chun-Li Su, Chung-Wei Huang, Hsiao-Sheng Liu, Chun-Nan Lin and Shen-Jeu Won

in Carcinogenesis

Volume 26, issue 10, pages 1716-1730
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi133
Justicidin A decreases the level of cytosolic Ku70 leading to apoptosis in human colorectal cancer cells

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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 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: cyto c, cytochrome c; DFF, DNA fragmentation factor; Δψm, mitochondrial membrane potential; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly(ADP-ribose) polymerase; PBMCs, human peripheral blood mononuclear cells; PI, propidium iodide; RACK1, receptors for activated C-kinase; s.c., subcutaneously; Smac, second mitochondria-derived activator of caspase/direct IAP binding protein with low pI; XIAP, X-linked apoptosis-inhibiting protein

Journal Article.  8352 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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