Tumor suppressor XIAP-Associated factor 1 (XAF1) cooperates with tumor necrosis factor-related apoptosis-inducing ligand to suppress colon cancer growth and trigger tumor regression.
BACKGROUND
XIAP-associated factor 1 (XAF1) antagonizes the anticaspase activity of XIAP (X-linked inhibitor of apoptosis) and functions as a tumor suppressor in colon cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known as a potential anticancer agent. In this study, the synergistic effect of XAF1 and TRAIL on colon cancer growth was investigated.


METHODS
Adeno-XAF1 virus was generated and purified. Cell apoptosis was detected by flow-cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Protein expression of the different genes was determined by Western blot analysis. Tumorigenesis and tumor growth were assessed in subcutaneous nude mouse xenograft experiments.


RESULTS
Stable overexpression of XAF1-sensitized colon cancer cells to TRAIL-induced apoptosis significantly increased the activity of caspase 3, 7, 8, and 9; released cytochrome c; and down-regulated XIAP, survivin, and c-IAP-2. The restoration of XAF1 expression mediated by adenovirus (adeno-XAF1) directly induced apoptosis, and synergized TRAIL-induced apoptosis in colon cancer cells. Ex vivo transduction of adeno-XAF1 suppressed colon cancer formation in vivo. Furthermore, adeno-XAF1 treatment of mice significantly inhibited tumor growth, strongly enhanced TRAIL-induced apoptosis and antitumor activity in colon cancer xenograft models in vivo, and markedly prolonged the survival. Notably, the combined treatment with adeno-XAF1 and TRAIL completely eradicated the established tumors without detectable toxicity in normal tissue.


CONCLUSIONS
The combined restoration of XAF1 expression and TRAIL treatment may be a potent strategy for colon cancer therapy.
Tu
Shui Ping
SP
Department of Gastroenterology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. tushuiping@yahoo.com
Sun
Yun Wei
YW
Cui
Jian Tao
JT
Zou
Bing
B
Lin
Marie C M
MC
Gu
Qing
Q
Jiang
Shi Hu
SH
Kung
Hsiang Fu
HF
Korneluk
Robert G
RG
Wong
Benjamin C Y
BC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C417551:XAF1 protein, human