Justicidin A decreases the level of cytosolic Ku70 leading to apoptosis in human colorectal cancer cells.
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.
Lee
Jenq-Chang
JC
Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Lee
Chao-Hung
CH
Su
Chun-Li
CL
Huang
Chung-Wei
CW
Liu
Hsiao-Sheng
HS
Lin
Chun-Nan
CN
Won
Shen-Jeu
SJ
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D016572:Cyclosporine; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004148:Dioxolanes / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D000072200:Ku Autoantigen; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms; D051028:bcl-2-Associated X Protein
D034961:Antigens, Nuclear; C494826:BAX protein, human; C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D004148:Dioxolanes; D017705:Lignans; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C049719:justicidins; D016572:Cyclosporine; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen